Chapter 160. Rheumatoid Arthritis, Rheumatic Fever, and Gout

This chapter discusses common rheumatologic diseases that have predominantly musculoskeletal presentations; however, all of these conditions have cutaneous manifestations.

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease that is characterized by a debilitating chronic, symmetric polyarthritis with significant extra-articular manifestations, which include rheumatoid nodules, pyoderma gangrenosum, granulomatous dermatitis, vasculitis, and internal organ involvement. The disease process is often progressive, resulting in limitation of joint function. Ultimately, there may be a resultant decline in functional status, possibly leading to premature death. Permanent remission is unusual.

Epidemiology

Rheumatoid arthritis has an annual incidence of approximately 0.4 per 1,000 in females and 0.2 per 1,000 in males, with a prevalence of approximately 0.4% to 1% of the adult population in diverse populations worldwide.1–3 Approximately 70% of patients follow a chronic disease course with exacerbations and remissions; 25% have intermittent disease with brief attacks of inflammation followed by remissions; approximately, 5% have an aggressive, malignant form with multiple extra-articular manifestations.4 RA has a peak onset at 50 years of age.1,2

Etiology and Pathogenesis

The exact etiology of RA remains unknown. Genetics plays at least some role in the development, severity, and outcome of the disease in certain patients.5 Furthermore, an association between extra-articular disease and HLA-DR1 and -DR4 genes has been noted in some populations.6

Mechanical stress on joints may initiate an inflammatory response creating an imbalance between the rapid response to trauma and the need to protect self from damage. Patients with seropositive RA (positive rheumatoid factor) have circulating and tissue-bound immune complexes. B cells produce autoantibodies in some RA patients. After binding to antigen, these autoantibodies result in complement fixation and recruitment of polymorphonuclear leukocytes, which result in joint destruction. Possible antigens in RA include heat shock proteins, collagen, and cyclic citrullinated peptides.7 Indeed, antibodies to several citrullinated peptides are enriched in the joints of patients with RA.8

Patients with negative rheumatoid factor (seronegative RA) may not create autoantibodies, but other immune mechanisms are involved. This theory led to the recognition that T cells are important players in the etiology of this disease. In the SKG mouse model, autoreactive T cells are preferentially selected, leading to inflammatory arthritis similar to RA. T cells also activate other cells via cytokines, including osteoclasts, which play a major role in the bone resorption seen in RA. Effector cytokines of the T cell include interferon-γ, interleukin 1, interleukin 17, and tumor necrosis factor-α (TNF-α), many of which have been, or are being, used as therapeutic targets to treat RA.4,7

Lastly, joints have unique anatomic and physiologic qualities that render them targets for immune and inflammatory assault. Cartilage is subject to repetitive mechanical stress, retains antigens and proinflammatory cytokines, and has a limited capacity for regeneration. Only two groups of enzymes found in the joint are capable of degrading native type I and II collagen fibrils: (1) cysteine cathepsins and (2) matrix metalloproteinases.9

Clinical Features

RA often begins with general constitutional symptoms such as fatigue, anorexia, vague musculoskeletal complaints, and generalized weakness. It may be weeks or months before the characteristic synovitis presents. It is in these early stages that definite diagnosis is most difficult, despite a thorough patient evaluation. However, early diagnosis and treatment are essential because most of joint damage is thought to occur early in the disease process. The American College of Rheumatology has guidelines for the diagnosis of RA (Table 160-1).10 For a patient to be diagnosed with RA, four of the seven criteria must be present, and the first four criteria listed must be present for at least 6 weeks. Extra-articular manifestations may help to delineate the disease process early and may signify a more serious disease process requiring the initiation of aggressive therapy.11,12 Several conditions can mimic RA, and must be considered in the differential diagnosis of early disease: viral syndromes (especially parvovirus B19, rubella, hepatitis B and C), polymyalgia rheumatica, remitting seronegative symmetric synovitis with pitting edema (RSSSPE), palindromic rheumatism, adult Still's disease, systemic lupus erythematosus, and multicentric reticulohistiocytosis.13

Articular Manifestations

The articular manifestations of RA relate to an inflammatory synovitis that can affect the synovial lining of joints, tendons, and bursae. Synovial inflammation usually results in warmth but not erythema of the affected area. There is significant pain in association with stretching of the joint capsule. Hand and foot involvement forms the basis of the disease in most patients. Although the initial manifestations in the hand may be asymmetric, the clinical course subsequently takes on a symmetric and diffuse pattern. There is a characteristic involvement of the proximal interphalangeal (PIP) and metacarpophalangeal joints with sparing of the distal interphalangeal (DIP) joints. The pattern of joint involvement is highly suggestive of the diagnosis.

Chronic inflammation may result in irreversible structural damage of the joint, including cartilage destruction and bony erosion. Late structural deformities may result from soft-tissue contractures or from bony ankylosis. Characteristic deformities include radial deviation of the hand with ulnar deviation of the digits, the “swan neck” deformity from hyperextension of the PIP joint and compensatory flexion of the DIP joint, and the boutonnière deformity from flexion contracture of the PIP joint and extension of the DIP joint. Similar structural deformities can occur in the feet, and all can be debilitating. Involvement of the thoracic and lumbar spine in RA is exceptional. Although the shoulder joint is often affected, it is soft-tissue structures, which include the rotator cuff tendons and muscles and the subacromial bursa that are usually involved in the patient's symptomatology.

Dermatologic Manifestations

Extra-articular manifestations occur in more aggressive or extensive forms of RA.11,12 The most common dermatologic finding in RA is the rheumatoid nodule. The classic rheumatoid nodule is a subcutaneous nodule that occurs in approximately one-fourth of patients with RA (Fig. 160-1A). More than 90% of patients with rheumatoid nodules have seropositive RA. The usual location is over pressure points such as the olecranon, the extensor surface of the forearms, and the Achilles tendon; but they have been described in almost every location, including viscera.12 The main histologic findings (see Fig. 160-1B) are palisaded granulomas in the deep dermis or subcutaneous tissues with fibrinoid degeneration of collagen, a multitude of neutrophils, and neutrophilic dust, with surrounding fibrosis and proliferation of vessels. The main differential diagnoses histopathologically include subcutaneous granuloma annulare, necrobiosis lipoidica, foreign body or infectious granulomatous reaction, and epithelioid sarcoid.14

Though rheumatoid nodules are benign, they can lead to complications, including ulceration, infection, joint effusion (rheumatoid chyliform bursitis), and fistulas (fistulous rheumatism). All conditions may lead to the need for surgical excision.12

Rheumatoid vasculitis has an estimated annual incidence of less than 1%, most often affects patients with seropositive disease, and is believed to affect 1 in 8 males with RA, versus 1 in 38 females.15 A study of 30-year cumulative incidence of extra-articular manifestations, major cutaneous vasculitis occurred in 5.1% of the study population.16 Small- to medium-sized vessels are primarily affected, often with associated peripheral neuropathy (including motor), digital gangrene, nail fold infarcts, and palpable purpura (see Chapter 163 and 164).12,17 Some patients may have nail fold telangiectasias, with minute digital ulcerations or petechiae and digital pulp papules (Bywaters lesions) (Fig. 160-2). These papules are a manifestation of mild vasculitis and typically occur without systemic signs of vasculitis. Histopathology of skin biopsy specimens usually shows leukocytoclastic vasculitis with neutrophilic infiltration of the vessel wall, fibrinoid necrosis, and hemorrhage without palisaded granulomatous reaction.14 Cutaneous small-vessel vasculitis mostly involves postcapillary venules and may affect arterioles and larger vessels of the viscera, heart, and central nervous system. The spectrum of clinical lesions reported in rheumatoid vasculitis is wide and varies with the size and location of the vessels involved and with the extent of the disease (see Chapters 163 and 164). Unfortunately, the presence of vasculitis, especially at the onset of the disease, portends a poor outcome.18 Vasculitis, along with certain other extra-articular manifestations of RA (pericarditis, pleuritis, amyloidosis, and Felty syndrome), are associated with a diminished lifespan.16 Rheumatoid vasculitis can present as lower-extremity ulcers; however, pyoderma gangrenosum (see Chapter 33) should be suspected if deep liquefying ulcers with a characteristic purple, undermined border occur in patients with RA. The ulcers may occur at any site but are most common on the lower extremities and abdomen. Pyoderma gangrenosum occurs more frequently and more severely in females and may take years to heal. Leg ulcers may also appear in patients with Felty syndrome, a combination of chronic RA, hypersplenism, and leukopenia (Fig. 160-3).12 In some instances, the ulcers of Felty syndrome exhibit the same morphologic characteristics and behavior of pyoderma gangrensoum ulcers, suggesting that these ulcers are not necessarily a manifestation of rheumatoid vasculitis.

Rheumatoid neutrophilic dermatosis is a very rare cutaneous manifestation in patients with severe RA. First described by Ackerman in 1978, these lesions are usually chronic, erythematous, and urticaria-like plaques and papules that are sharply marginated (Fig. 160-4A). Histopathologically, these lesions have a dense infiltrate of neutrophils without leukocytoclasia, in the setting of a mixed infiltrate and papillary edema (see Fig. 160-4B).14 It may be difficult to differentiate rheumatoid neutrophilic dermatosis from acute febrile neutrophilic dermatosis (Sweet syndrome) (see Chapter 32). Some authors accept palisaded neutrophilic granulomatous dermatitis as a histologic finding consistent with rheumatoid neutrophilic dermatitis.19 However, in the absence of granuloma formation, it seems reasonable to separate rheumatoid neutrophilic dermatitis from multiple named entities, which would seem to be now included under the term interstitial granulomatous dermatitis.

Other vasculitis syndromes, such as erythema elevatum diutinum (see Chapter 165) and livedo vasculitis (segmental hyalinizing vasculitis), have also been described in patients with RA. Skin manifestations such as palmar erythema, erythromelalgia, autoimmune bullous diseases such as epidermolysis bullosa acquisita (see Chapter 60), yellow nail syndrome (see Chapter 89), erythema multiforme (see Chapter 39), erythema nodosum (see Chapter 70), and urticaria (see Chapter 38) also have been reported in patients with RA.20

Low-dose methotrexate, often used for the treatment of rheumatoid arthritis, may precipitate erythema and enlargement of preexisting rheumatoid nodules, known as accelerated nodulosis.21 Regression of these changes is expected when the methotrexate dose is decreased or discontinued. A second reaction to methotrexate has also been reported as a syndrome of clustered, erythematous, indurated papules arising most commonly on the proximal extremities and buttocks. This has been reported not only in patients with rheumatoid arthritis, but also in association with other diseases as well, especially collagen vascular diseases.22,23 In rare instances, some lesions may develop erosions or surrounding livedo. The histologic pattern seen in the popular eruption is that of a mostly histiocytic infiltrate arranged interstitially between collagen bundles in the dermis, intermixed with a few neutrophils. Small rosettes of histiocytes may surround thick collagen bundles in the reticular dermis. Yet another possible cutaneous complication of methotrexate therapy in rheumatoid arthritis is the development of Epstein–Barr virus-associated multifocal cutaneous lymphoproliferative disease, which may regress on discontinuation of therapy.24

A histologically related eruption of interstitial granulomatous dermatitis has been described in association with a number of disorders, including rheumatoid arthritis.23 Cutaneous lesions consist of linear slightly red or skin-colored cords, most often extending from the upper back to the axillae.23,25 Histopathologic findings include a dense, diffuse infiltrate of histiocytes arranged in a band-like configuration in middle or deep reticular dermis. There may be foci of basophilic collagen surrounded by palisaded histiocytes. These cells may also exhibit large and pleomorphic nuclei, and scattered mitotic figures are readily seen. Neutrohils and eosinophils are present, most notably in areas of degenerated collagen.

Indurated erythema, livedo-like erythema, and papules over the elbows have been reported as clinical findings of intravascular or intralymphatic histiocytosis in rheumatoid arthritis.25

Nondermatologic Extra-Articular Manifestations

In addition to systemic vasculitis, which can affect numerous organ systems, there are multiple nondermatologic extra-articular manifestations of RA. Table 160-2 lists the more common ones.

Differential Diagnosis of Rheumatoid Nodules

(Box 160-1)

Laboratory Findings

There is no one specific histologic, radiographic, or laboratory test that conclusively permits the diagnosis of RA. Rheumatoid factor, an autoantibody that reacts with the Fc portion of immunoglobulin G (IgG), is found in sera of 85% of patients with RA. Rheumatoid factor should not be used as a definitive screening tool because it can be found in other disease processes (sarcoidosis, liver diseases, pulmonary fibrotic processes, and cryoglobulinemia). It is also found in approximately 5% of the unaffected population.17 A false-positive rheumatoid factor can be caused by many factors, including chronic bacterial infections such as infective endocarditis, tuberculosis, and Lyme disease, as well as by viral diseases such as rubella and infectious mononucleosis.26 Anticitrullinated protein antibodies have been shown to be a more specific marker than rheumatoid factor, particularly in early disease where specificity ranges from 94% to 100%, compared to 23% to 94% for rheumatoid factor, with roughly equivalent sensitivities.3

Treatment

Because the exact cause of RA is unknown, treatment has been directed against various components of the inflammatory process. No single therapy is the treatment of choice. In the past, most patients with early disease were started on nonsteroidal anti-inflammatory drugs until joint erosions were evident.

These medications are useful to alleviate symptoms. They do not alter disease progression.

Furthermore, new understanding of disease mechanism and the chronic disabling nature of RA have resulted in a shift to earlier use of disease-modifying antirheumatic drugs (DMARDs). New guidelines released by the American College of Rheumatology in 200218 advocate this switch.27 DMARDs decrease inflammation (confirmed by a reduction in acute-phase reactants), reduce or prevent joint damage, and modify the disease process. The use of DMARDs is now recommended early in the disease course, when joint damage has already occurred or is imminent. Multiple medications fall into this category (Table 160-3). They may be used alone or in combination, but their use may be limited by loss of efficacy or systemic toxicity. Medications are often used in combination, but the decision about which drug to use is often individualized and determined by the clinical severity and loss of function and resultant disability, along with concerns about the safety profile of each given patient.

Systemic glucocorticoids are potent anti-inflammatory agents but have a serious side-effect profile when used in large doses over long periods of time. They are not a good option alone for RA, but are sometimes used in a low dose with other DMARDs. Methotrexate has been used as a very effective DMARD for many years, and is often the standard of care for initial DMARD therapy of RA.28,29 Other nonbiologic DMARDs include hydroxychloroquine sulfate, sulfasalazine, leflunomide, gold salts, azathioprine, cyclosporine, and minocycline.

The newest additions to the antirheumatic armamentarium are the biologic response modifiers, which act to inhibit the proinflammatory cytokines that play a role in RA. The best known commercially available members of this category are the anti-TNF-α agents. TNF-α is a proinflammatory agent released by macrophages and T cells contributing to synovitis and joint destruction.

There are five anti-TNF-α drugs currently approved by the US Food and Drug Administration, which have been used in the treatment of RA: (1) etanercept, (2) infliximab, (3) adalimumab, (4) golimumab, (each approved for use in RA), and (5) certolizumab (approved for use in Crohn disease).28 Etanercept is a recombinant human TNF dimeric receptor fusion protein consisting of the ligand-binding portion of the human 75-kDa TNF receptor linked to the Fc portion of human IgG1. This treatment is given as a subcutaneous injection twice per week. Infliximab is a chimeric (mouse/human) IgG1 monoclonal antibody to TNF-α. It is given intravenously every 6 to 8 weeks. Adalimumab is a human IgG1 monoclonal antibody that binds membrane bound and soluble TNF-α. Adalimumab, like other TNF inhibitors, commonly induces autoantibodies, but only rarely induces autoimmune diseases, such as lupus.30 Golimumab, a human monoclonal antibody, is the newest TNF inhibitor approved for use in rheumatoid arthritis, administered as a once monthly subcutaneous injection.31 Certolizumab is a humanized, pegylated, Fc-free anti-TNF monoclonal antibody, which has been used alone or in combination with methotrexate in rheumatoid arthritis. These agents render TNF-α biologically inactive, thereby significantly decreasing the synovitis and retarding the progression of joint destruction.32 Cutaneous vasculitis presumed secondary to RA has been reported in three patients treated with anti-TNF agents.33 An apparent rare class effect of TNF inhibitors is the development of sarcoidosis in patients with psoriatic or rheumatoid arthritis.34

Other biologic DMARDs include rituximab (CD20 monoclonal antibody), abatacept (T-cell activation inhibitor, anakinra (IL-1 receptor antagonist), and tocilizumab (an IL-6 receptor antagonist).28 Rituximab is commonly given with methotrexate or another nonbiologic DMARD, and is administered as two 1,000-mg intravenous infusions given 2 weeks apart.28 Rituximab has been helpful in patients refractory to TNF blockade.35 Pretreatment with methylprednisolone 50–100 mg infused 30 minutes beforehand may mitigate infusion reactions. Cutaneous vasculitis has been reported as a rare association with rituximab therapy.36 Ofatumumab is also an anti-CD20 monoclonal antibody approved for use in chronic lymphocytic leukemia, which has been used in some patients with DMARD-resistant rheumatoid arthritis.37 Abatacept is a fusion protein that interferes with T-cell activation, given as an initial IV dose, then at week 2 and 4, then monthly thereafter. Infusion reactions may occur within an hour after infusion. Increase in pneumonia, pyelonephritis, cellulitis, and diverticulosis is suspected, but increase in tuberculosis is not documented.28,38 Anakinra competitively inhibits the interleukin-1 effects, but is currently felt to be the least effective biologic DMARD for RA.28 Tocilizumab may achieve clinical improvement within a few weeks. Adverse effects include hypertension, neutropenia, elevated transaminases, dyslipidemia, and rarely GI perforation, serious infection, or anaphylaxis.

There are a number of limitations to the use of biologic response modifiers. They are expensive, ranging between 18,000 to 30,000 dollars per year, and both etanercept and adalimumab require the patient to self-administer injections. Not all patients are willing to do this. Injection site reactions are common with etanercept and adalimumab. Infliximab, on the other hand, is an infusion, which inherently requires that the patient has more time from work/home and lends itself to the possibility of infusion reactions, including fever, urticaria, dyspnea, and hypotension. In addition, there needs to be an infusion center nearby where the patient can receive therapy. Most patients receiving TNF-α-blocking agents have failed therapy with one or a combination of the previously mentioned DMARDs. Inhibiting the normal host immune response has led to concern about reactivation of tuberculosis, increased susceptibility to other infections, and predisposition to the development of malignancy. The true risk of malignancy is difficult to establish because patients with RA are thought to have a higher incidence of lymphoid malignancy than the normal population, and some have shown that the incidence of lymphomas may in fact be increased in patients taking anti-TNF-α drugs.39 As with all medications, knowing your patient's medical history is the key to proper use of these medications. They should not be used in patients with concurrent serious infection or in those predisposed to serious infections (patients with poorly controlled diabetes). Extreme caution and consultation with the hematologist-oncologist should be used before prescribing these medications to patients with a recent history of malignancy.

In conclusion, the dermatologist and rheumatologist must function as a cohesive team in the treatment of patients with cutaneous manifestations of RA, which often present during phases of intense disease activity. Patients need their underlying rheumatic disease to be treated aggressively, but proven treatments for these associated dermatologic processes, such as pyoderma gangrenosum, cryoglobulins, vasculitis, and others, should not be forgotten. These specific treatment regimens are beyond the scope of this chapter.

In 1995, the International League of Associations for Rheumatology (ILAR) Task Force on the Classification of Childhood Arthritis proposed juvenile idiopathic arthritis (JIA) for all chronic childhood arthritides of unknown cause, beginning before age 16 and persisting for at least 6 weeks, and encompassing previous terms including juvenile rheumatoid arthritis and Still's disease.40 Using their criteria, JIA can be diagnosed as early 6 weeks after the onset of symptoms, while the assignment to a specific JIA category requires a disease duration of up to 6 months These categories include systemic arthritis, oligoarthritis, RF-negative polyarthritis, RF-positive polyarthritis, psoriatic arthritis, enthesitis-related arthritis, and others.40 The expression adult-onset Still's disease (AOSD) was introduced by Bywaters in 1971 to characterize 14 women with seronegative polyarthritis, rash, fever, and raised erythrocyte sedimentation rate.41 This syndrome most often affects younger adults, and females more often in Eastern than in Western countries. The classical adult presentation includes high spiking fever, an evanescent salmon pink rash, and arthritis, often accompanied by sore throat, myalgias, lymphadenopathies, splenomegaly, and neutrophilic leukocytosis.42 High fever of unknown origin (FUO) exceeding 39°C is the presenting sign of AOSD in 95% of patients, but only 5% of all persons with FUO have AOSD.41 Classically, patients present with one to two daily fever spikes above 39°C occurring in the afternoon or evening and receding within hours. Musculoskeletal pain is often present, including myalgia (20%–90%), arthralgia (27%–100%), and arthritis (18%–82%).41 Multiple arthritis patterns may occur, but polyarticular and symmetric involvement affecting knees, wrists, fingers, and ankles is most common.

A rash may be seen in 25% to 100% of patients.41,42 It is seen more often in the febrile presentation than in the solely arthritic form of disease. It most characteristically occurs on the chest, abdomen, and extensor surfaces of the arms, and tends to peak with the fever in the late afternoon, and then disappears, only to recur with fever the following day.41,43 The rash consists of discrete pink to red macules or slightly edematous papules ranging in size from 5 to 10 mm. The lesions tend to be relatively fixed in shape and site during their daily eruption and seldom itch. Koebner phenomena may be seen. Histologic findings include dermal edema, a mild mostly lymphocytic perivascular infiltrate that may include a few neutrophils. In some patients, the lesions may demonstrate prominent perivascular neutrophilic infiltrates, sometimes involving dermis but without the edema typical of Sweet lesions, with leukocytoclasia but without vasculitis. This finding has been reported as neutrophilic urticarial dermatosis, and found in association with autoinfammatory diseases, Schnitzler syndrome, hepatitis C, asthma, and adult-onset Still's disease.44

Two unusual syndromes appear to be associated with AOSD: (1) thrombotic thrombocytopenic purpura and (2) reactive hemophagocytic syndrome.45,46 Both are rare, and the reason for association unclear, but each syndrome has multiple reports supporting these as a complication of AOSD.

Laboratory findings include an increased sedimentation rate, leukocytosis with neutrophilia, hypoalbuminemia elevated hepatic enzymes, anemia (<10 g/dL), and thrombocytosis, in decreasing order of frequency. Antinuclear antibody and rheumatoid factor are negative in most patients. More recently, a very elevated serum ferritin with a lowered concentration of glycosylated ferritin, has been seen as strongly suggestive of, but not specific for, this diagnosis.41,42 Very high levels of serum ferritin between 3,000 and 30,000 ng/mL (normal range 40–200 ng/mL) are not uncommon, and levels above 250,000 ng/mL have been reported.42 A threshold level of 1,000 ng/mL appears to offer an 80% to 82% sensitivity and 41% to 46% specificity for a diagnosis of AOSD. Perhaps more specific is the fraction of glycosylated ferritin. In healthy individuals, 50% to 80% of serum ferritin is glycosylated, but this drops to 20% to 50% in patients with inflammatory diseases.42

Acute disease is often treated with nonsteroidal anti-inflammatory agents, particularly enteric-coated aspirin, while some begin with corticosteroid and most would use corticosteroids if NSAID therapy is ineffective. A variety of second-line drugs has been used: intramuscular gold, d-penicillamine, sulfasalazine, hydroxychloroquine, methotrexate, thalidomide, azathioprine, cyclosporine, cyclophosphamide, intravenous immunoglobulins, anti-TNF agents, anakinra, rituximab, and tocilizumab (an IL-6 receptor inhibitor) are reported as sometimes effective.41,42,47

Acute rheumatic fever (ARF) is a delayed sequel to group A β-hemolytic streptococcal (GAS) infection of the oropharynx. It is an inflammatory disease that can affect the heart, joints, central nervous system, skin, and subcutaneous tissues. There are no specific diagnostic tests, rather it is a clinical diagnosis made on the basis of certain criteria. Treatment of the underlying infection leads to prevention of rheumatic fever.

Epidemiology

ARF is rare and most commonly occurs in children 5 to 15 years of age after clinically severe tonsillopharyngeal infections. However, it has been reported in patients of all ages and in those with asymptomatic disease. The incidence of rheumatic fever has decreased since the beginning of the twentieth century, and dropped precipitously since the 1950s with widespread recognition of disease and treatment with penicillin. It has been nearly eradicated from the developed world but remains a serious health problem in developing countries. Currently, the average incidence in most developed communities is less than 5/100,000 population.48,49 Rates of 72 to 150/100,000 have been reported in countries with sizable less affluent populations, where overcrowding and poorer public hygiene may play a role. The World Health Organization estimates that 15.6 million people worldwide are affected by rheumatic heart disease, and that 233,000 people die annually either from rheumatic heart disease or acute renal failure as a result of complicated GAS infection.48,49

Pathogenesis

The exact mechanism by which ARF results from an infection with group A streptococcal bacteria is unclear, but it is thought to be an exaggerated immune response to infection. Some strains of streptococcus are more likely to cause ARF than others. For instance, pharyngeal strains are much more likely to cause ARF than extrapharyngeal strains responsible for impetigo or cellulitis.48 Molecular mimicry has also been implicated in the etiology of ARF. M protein has structural similarity to cardiac myosin. Studies have demonstrated that rats immunized with streptococcal M protein develop myocarditis. Oddly, however, the morbidity and mortality of rheumatic fever results from valvular disease rather than acute carditis.49 Familial clustering of disease, and the linkage of HLA-DR4 and -DR2 to ARF in Caucasian and African-American patients demonstrates that host properties also affect the susceptibility of individual patients in the development of disease.48

Clinical Features

The clinical features of ARF vary widely and are largely outlined in the Jones criteria used to aid in diagnosis of the disease. The Jones criteria, updated in 1992,50 emphasize five characteristic major manifestations: (1) polyarthritis, (2) carditis, (3) chorea, (4) subcutaneous nodules, and (5) erythema marginatum (Box 160-2). Nonspecific signs of systemic inflammation are considered minor criteria and include arthralgia, fever, elevated acute-phase reactants, and a prolonged P–R interval by echocardiogram.

Diagnosis is based on the presence of two major criteria and one minor criteria plus evidence of preceding infection with group A Streptococcus. If, however, chorea and carditis are present then demonstration of antecedent strep infection is not required to make the diagnosis.50 There is some evidence that a revision of the Jones criteria should be considered, particularly in endemic areas.51 These might include monoarthritis, subclinical carditis, and a low-grade fever, (≥37.5), in order to avoid an important subset of patients who develop cardiac complications but do not meet standard Jones criteria.

Rheumatic carditis usually involves the endocardium, myocardium, and pericardium and almost always is associated with a murmur, either mitral or aortic regurgitation.49 Carditis, if present, usually presents in the first 3 weeks of the illness. There has been much debate about the use of echocardiography to aid in diagnosis of rheumatic heart disease without clinical evidence of a murmur; however, thus far its routine use has not been advocated. Its use has been accepted in patients with polyarthritis where other diagnostic criteria have not yet been met and in indistinguishable heart murmurs.49

Migratory polyarthritis can affect any joint but most often involves the large joints. Early administration of anti-inflammatory medications does mitigate the arthritis and may therefore mask it. In addition, poststreptococcal reactive arthritis exists and can confound the picture.49 The diagnosis of chorea is based entirely on clinical signs, which include fleeting local muscular weakness, emotional lability, personality changes, and erratic, jerky, purposeless movements. Chorea does not occur in adult men.

The dermatologic manifestations of ARF are characteristic but rare. Subcutaneous nodules are small, painless, and localized over bony prominences and in tendon sheaths. They are usually smaller, more discrete, and less persistent than rheumatoid nodules, and are usually seen in children with prolonged active carditis, rather than in the early stages of rheumatic fever.48 These resemble histologically the Aschoff nodules seen in the heart.48 Typically, they last for 1 to 2 weeks and spontaneously resolve. Erythema marginatum begins as an erythematous macule or papule extending outward while the central skin returns to normal. The border is pink and serpiginous, is not indurated, and blanches with pressure (Fig. 160-5). Patients are often unaware of its presence. Histopathologically, there is a sparse superficial perivascular infiltrate of lymphocytes and neutrophils.14,48

Treatment

Treatment is directed at eradication of GAS from the oropharynx. Penicillin is the antibiotic of choice, is inexpensive, and can be administered orally or intramuscularly. Oral therapy should be continued for at least 10 days.48 Penicillin-allergic patients can be treated with cephalosporins or macrolide antibiotics.21 Due to the high rate of recurrence in previously affected people, antibiotic prophylaxis is recommended, especially in endemic areas.

The acute inflammatory process is largely treated symptomatically, including bed rest during the early phase of the syndrome.48 Anti-inflammatory medications including salicylates and nonsteroidal agents are effective for the arthritis, fever, and arthralgia. However, salicylates alone have not been shown to be effective in decreasing the incidence of rheumatic heart disease after ARF. Corticosteroids are believed to be beneficial in the treatment of carditis; though this has never been shown in a randomized controlled trial. Lastly, intravenous Ig has also been tested but has not shown any benefit.19 Approximately 80% of patients who fulfill the criteria for this disorder recover spontaneously.

Gout is a clinical syndrome caused by a group of heterogeneous diseases characterized by deposition of monosodium urate crystals in synovial fluid and joints with or without hyperuricemia, renal disease, or nephrolithiasis.52,53 It tends to occur in both acute and chronic forms. Classically, the acute presentation is that of an acute lower extremity peripheral joint inflammatory synovitis. The most commonly affected sites are the first metatarsophalangeal joint and the ankle. In the chronic form, aggregates of crystals are deposited in tissue, especially in skin and around joints. While skin disease is often asymptomatic, periarticular and osseous deposition may lead to bone destruction.

Epidemiology

Gout affects approximately 5 million Americans and has historically been described as a disease that affects men; however, it also affects women. Recent epidemiologic studies demonstrate that on average, women develop gout a decade later than men, and that female patients with gout are more likely to have renal insufficiency or to be taking diuretics.22 Obesity has been linked to gout, and both diseases have increased in incidence over the past two decades. Alcohol has long been recognized as a risk factor for gout, but only recently consumption of purine rich foods such as meat and seafood has been shown to correlate positively with serum urate levels and gout. It has also been shown that eating low-fat dairy products may be protective.23 Gouty attacks in children are so uncommon that this diagnosis should prompt an evaluation for a malignant or genetic cause.

Pathogenesis

Hyperuricemia is a risk factor for gout, but acute gouty arthritis can occur in patients with normal serum uric acid levels. Patients with serum uric acid levels greater than 7 mg/dL have a 22% chance of developing gout over a 5-year period, demonstrating that many patients with elevated serum uric acid levels may never have gouty arthritis.6

Uric acid is the end product of purine catabolism. In most fish, amphibians, and nonprimate mammals, purine-generated uric acid is degraded through a uricase (a uric acid oxidase).53 In primate mammals and humans, the uricase gene is silenced by two mutations. This absence of uricase, along with extensive reabsorption of filtered urate, results in plasma urate levels that are 10 times that of most other mammals.53 Hyperuricemia results from either overproduction or underexcretion of uric acid. Ninety percent of affected patients are underexcreters.6

Table 160-4 presents a classification of hyperuricemia. Less than 10% of patients with hyperuricemia or gout excrete excessive quantities of uric acid in a 24-hour urine collection. It is usually in this group that identifiable and inherited derangements in mechanisms regulating protein nucleotide synthesis, specifically a deficiency of hypoxanthine-guanine phosphoribosyltransferase, glucose-6-phosphatase, or fructose-1-phosphatase, either partial or complete, can be found. These are genetically inherited by X-linked and autosomal recessive means (in the latter two); therefore, family history or early presentation may be a clue. The Lesch–Nyhan syndrome, well described but very rare, is an extremely severe form of hypoxanthine-guanine phosphoribosyltransferase deficiency associated with mental retardation, gout, and self-mutilation.26

Uric acid underexcretion is idiopathic in patients with hyperuricemia. The anatomic appearance and physiologic function of the kidney appear normal; however, alteration of renal tubular function in these patients by many drugs can precipitate gouty attacks. These pharmacologic agents include loop diuretics, low-dose cyclosporine, and salicylates.

Precipitating causes of an acute gouty attack are not well understood. Studies have shown the presence of intracellular monosodium urate crystals in synovial fluid of asymptomatic patients, suggesting that inflammation in gout is chronic. There must be an unidentified trigger in the acute attack that incites a more robust inflammatory response. Monocytes are present and secrete cytokines, including TNF-α, interleukin 1, interleukin 6, and interleukin 8. Neutrophils are then attracted to the site as well; they ingest the crystals, and release multiple inflammatory mediators, initiating further inflammation and tissue damage.53

Clinical Manifestations

It is felt that gout occurs in four stages: (1) asymptomatic hyperuricemia, (2) acute gouty arthritis, (3) intercritical gout (between gouty attacks), and (4) chronic tophaceous gout.26

Patients are often asymptomatic for years, requiring no therapeutic intervention in the absence of other evidence of disease (e.g., nephrolithiasis or renal insufficiency).

Acute gouty arthritis usually occurs in middle age and primarily affects a single joint in the lower extremities, the first metatarsophalangeal being the most common site of initial involvement (podagra).26,52 Clinically, the affected joint is erythematous and exquisitely tender to palpation. This may be confused with a sprain, a septic joint, or cellulites. Cytokine release can lead to fever and systemic symptoms, confounding the picture further. Further differential diagnoses include other forms of arthritis (psoriatic, reactive arthritis osteoarthritis, or RA) and pseudogout (chondrocalcinosis).26

Intercritical gout describes the interval that occurs between attacks of gout, an interval of between 6 months to 2 years. As attacks continue, they tend to be polyarticular, more severe, and of longer duration. Chronic tophaceous gout describes gout where patients rarely have asymptomatic periods. Urate crystals may be found in the soft tissues, cartilage, and tendons (Fig. 160-6A).26 They have been reported in a variety of unusual places as well, including the nasal dorsum.24 They may be confused with rheumatoid nodules, and aspiration or biopsy may prove useful.

Laboratory Presentation and Pathology

Laboratory analysis may reveal elevated uric acid levels, but this finding is not necessary for the diagnosis. Leukocytosis and elevated sedimentation rate are often seen during acute arthritic attacks. Accurate diagnosis rests on the demonstration of intracellular, negatively birefringent, needle-shaped crystals by polarized microscopy. Histopathologic examination of a gouty tophus reveals granulomatous inflammation surrounding yellow–brown urate crystals or needle-like spaces in a radial arrangement, representing crystals dissolved during processing (see Figs. 160-6B and 160-7).14

Treatment

The goal of therapy in acute gouty attacks is analgesia and reduction in inflammation. The main options to choose from are the nonsteroidal anti-inflammatory drugs, colchicine, and corticosteroids. Indomethacin has been shown in randomized controlled trials to decrease pain, as has colchicine; however, the adverse gastrointestinal side effect of colchicine is often a deterrent for its use. However, a newer regimen for colchicine use in acute attacks appears to greatly reduce the incidence of gastrointestinal symptoms.54 This regimen of 1.2 mg of colchicine followed in 1 hour by 0.6 mg, also is likely to reduce drug–drug interactions mediated by colchicine inhibition of P-glycoprotein and cytochrome 3A4 pathways. Severe adverse reaction and deaths have been reported when colchicine is combined with other strong inhibitors of one or both pathways (e.g., clarithromycin, erythromycin, and cyclosporine).54 Indomethacin can precipitate acute renal failure in patients with underlying renal disease. Corticosteroids, both oral and intra-articular, are also believed to be effective. Because patients with gout are older and often have many comorbidities, therapy should be individualized. Treatment should continue for 7 to 10 days after the acute attack, and prophylactic therapy may be continued for 3 to 6 months.26,52

In patients with only one gouty attack, a conservative management approach can be used. This includes avoidance of drugs that decrease the excretion of uric acid such as thiazide or loop diuretics, aspirin, pyrazinamide, or niacin. Patients should maintain adequate hydration, lose weight, control hypertension and hyperlipidemia, and make diet adjustments by decreasing purine intake. Effectiveness of limiting cholesterol, fat, meat, and alcohol has never been studied, but should be advocated to avoid the need for lifelong oral therapy.26,53

Uric acid-lowering therapy is probably necessary in patients in whom the diagnosis of gout has been established, and who have had more than one gouty attack or are suffering from chronic tophaceous gout. It is also indicated in patients with history of gout and renal calculi, extremely high values of serum uric acid, high serum uric acid levels in the setting of a known familial history of gout (e.g., where there is a known deficiency of one of the relevant enzymes previously described), and prophylaxis for patients receiving acute courses of chemotherapy.

The goal of urate-lowering drugs is to maintain the serum urate level consistently at less than 6 mg/dL. Uricosuric therapy is ideal in younger patients (age less than 60 years) with normal kidneys who are underexcreters of uric acid. Uricosurics include probenecid, sulfinpyrazone, and benzbromarone.55,56 The major risks associated with these medicines include hypersensitivity reactions and increased risk of uric acid nephrolithiasis (avoided by alkalinizing the urine). Unfortunately, most patients with gout do not fit this “ideal” situation. Benzbromarone is not commercially available in the United States and many other countries; though potent, it is potentially hepatotoxic.56

For all other patients, the xanthine oxidase inhibitors are used. Allopurinol is the first-line drug for serum urate lowering.55 It decreases production of uric acid, and is indicated for patients with nephrolithiasis, renal impairment, those who failed uricosuric agents, with myeloproliferative disorders on chemotherapy, and patients with hyperuricemia due to enzyme abnormalities. Dosages must be reduced in patients with renal failure. Twenty percent of patients taking allopurinol report side effects, and 5% discontinue medication as a result. Side effects include dyspepsia, headache, diarrhea, a pruritic papular eruption, thrombocytopenia, and hepatic function abnormalities. Allopurinol hypersensitivity syndrome is rare and includes fever, urticaria, leukocytosis, eosinophilia, interstitial nephritis, acute renal failure, granulomatous hepatitis, and toxic epidermal necrolysis. A second xanthine oxidase inhibitor is febuxostat, labeled for use at 40 mg once daily.55,56 It appears to be roughly equivalent to allopurinol. However, it does show higher efficacy in the setting of renal impairment, when allopurinol, but not febuxostate, must be reduced.56

Uricases are an additional class of therapeutic agents used in treating urate disorders. The nonpegylated recombinant fungal enzyme rasburicase is Food and Drug Administration (FDA) approved for short-course therapy to prevent tumor lysis syndrome.55 It is highly immunogenic, and its plasma half-life is less than 24 hours. Pegylation of uricases with production of PEG multimers has decreased the immunogenicity and increased the serum half-life to days or weeks. Infusion reactions may be seen, and include flushing, urticaria, hypotension, and anaphylaxis. All uricase therapies may induce oxidative stress, which can lead to methemoglobinemia or anemia, occurring more often but not confined to glucose-6-phosphate dehydrogenase-deficient (G6PD-deficient) individuals.55 The role of pegylated uricases in treating urate disease remains to be determined.