Jonathan J. Miner and Richard D. Brasington
Approach to the Patient with Painful Joints
GENERAL PRINCIPLES
· The initial evaluation of a patient with painful joints is focused on ruling out emergent versus nonemergent causes of arthritis.
· While early diagnosis and treatment of most causes of arthritis are important to ensure the best possible outcome, infectious causes of arthritis such as septic arthritis and endocarditis require emergent evaluation and treatment.
· A logical approach to the evaluation of painful joints includes categorizing as either monoarticular arthritis or polyarticular arthritis based on the number of joints involved.
DIAGNOSIS
An algorithmic approach to the diagnosis of monoarticular and polyarticular arthritis is presented in Figures 33-1 and 33-2, respectively.1
Figure 33-1 Evaluation of monoarticular arthritis. CBC, complete blood count; ESR, erythrocyte sedimentation rate; RA, rheumatoid arthritis; RF, rheumatoid factor; WBC, white blood cells. Modified from Guidelines for the initial evaluation of the adult patient with acute musculoskeletal symptoms. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum 1996;39:1–8.
Figure 33-2 Evaluation of polyarthralgia. Modified from Guidelines for the initial evaluation of the adult patient with acute musculoskeletal symptoms. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum 1996;39:1–8.
Clinical Presentation
History
· Characteristic inflammatory symptoms include swelling, heat, redness, morning stiffness, stiffness after inactivity (the so-called gelling phenomenon), and sometimes fever.
· Mechanical symptoms include pain with activity that is relieved with rest, minimal morning stiffness, joint locking or giving out, and lack of swelling or heat.
· Location of pain can help provide clues as to the etiology.
o History of precedent traumatic injury might suggest degenerative arthritis of the joint, whereas the classic presentation of podagra with inflammation of the first metatarsophalangeal (MTP) joint suggests gout.
o Osteoarthritis (OA) tends to affect knees, hips, and the first carpometacarpal joint in the hand.
o Multiple pain complaints and diffuse tender points suggest a chronic pain syndrome such as fibromyalgia or depression.
Physical Examination
· Gait: Observing the patient walking away, turning, and walking back can help localize the source of pain.
· Hand: Have the patient make a fist and inspect the dorsum of the hand; observe supination; and inspect the palm of the hands. Look carefully at each of the joints, and palpate the metacarpophalangeal joints for swelling or tenderness.
· Shoulder: Ask the patient to put both hands together above the head and observe any abnormal movement of the scapula; put both hands behind the head; and put both hands behind the back (normally, the thumb tip can reach the tip of the scapula).
· Cervical spine: Have the patient touch the tip of the chin to chest, look up, and look over each shoulder.
· Lower spine: Ask the patient to bend forward to touch the toes without bending the knees, and observe movement of the lumbar spine (normally, there should be reversal of lordosis with flexion of the lumbar spine).
· Hip: The FABER maneuver (flexion-abduction-external rotation) is performed by first having the patient put his or her heel on the contralateral knee; the examiner then presses down on the medial knee, putting the hip into external rotation. The important finding is where pain is elicited. Pain in the groin is indicative of hip joint pathology, but pain may also be elicited from the SI joint and the lateral aspect of the hip from the trochanteric bursa.
· Knee: The patient should be able to straighten the knee fully and flex it so the heel almost touches the buttocks. Look for symmetry and effusions. The patella can be held in place with one hand and normally should have little give. In the presence of an effusion, one can elicit a bulge sign.
· Ankle: One should look for limitations in flexion and extension and inversion and eversion.
Diagnostic Testing
Laboratories
· Few rheumatology tests are designed to serve as independent diagnostic tools, and test results must always be interpreted in a clinical context.
· Erythrocyte sedimentation rate (ESR) is a very nonspecific indicator of inflammation and is often elevated due to increased fibrinogen during inflammation. Anemia, kidney disease (especially proteinuria), and aging can all elevate the ESR in the absence of inflammation.
· C-reactive protein (CRP) is an acute-phase reactant and a component of the innate immune system; levels rise rapidly with inflammation and infection and fall quickly as inflammation resolves.
o Unlike the ESR, the CRP is not influenced by anemia and abnormal erythrocytes.
o Today, most laboratories perform a high-sensitivity assay for the presence of CRP that can identify minute increases.
· Rheumatoid factor (RF) is an immune complex of immunoglobulin (Ig) M that binds to the Fc portion of IgG and is elevated in approximately 80% of patients with rheumatoid arthritis (RA). However, RF can also be elevated in Sjögren syndrome, sarcoidosis, chronic infections, and other conditions where immune complexes are formed.
· Anticitrullinated protein antibodies (ACPA or anti-CCP) recognize a posttranslational modification of proteins that is thought to occur in the synovium of patients with RA. The assay is now routinely performed, has a higher specificity for the diagnosis of RA, and may be predictive of progressive joint disease.2
· Antineutrophil cytoplasmic antibody (ANCA): ANCA detects antibodies against neutrophils and is reported as either a cytoplasmic pattern (c-ANCA) or a perinuclear pattern (p-ANCA).
o A positive ANCA test is only significant when confirmatory ELISA demonstrates that the c-ANCA represents anti–proteinase-3 (PR3) or the p-ANCA represents antimyeloperoxidase (MPO).
o Antibodies against PR3 are specific for granulomatosis with polyangiitis (GPA, formerly known as Wegener granulomatosis).
o Antibodies against MPO are less specific and are seen in conditions such as microscopic polyangiitis and Goodpasture syndrome (in up to 30% of patients).
· The antinuclear antibody (ANA) test detects antibodies that bind to nuclear antigens. ANA is a very sensitive test for patients with systemic lupus erythematosus (SLE, sensitivity >95%) and may be abnormal in many other autoimmune diseases such as scleroderma, Sjögren syndrome, and polymyositis. However, because the specificity of the ANA is low, a positive ANA alone is seldom useful. Furthermore, this highly sensitive test produces many confusing false positives and should only be obtained in patients whose clinical presentation suggests lupus or a related disease.
· Antibodies to extractable nuclear antigens (ENA): This test encompasses a panel of saline-soluble nuclear antigens. This panel detects four autoantibodies: anti-SM (Smith, SLE), anti-RNP (ribonucleoprotein, SLE, and mixed connective tissue disease), and SSA and SSB (Sjögren syndrome, SLE, and neonatal lupus). SSA and SSB are also known as anti-Ro and anti-La, respectively.
· Anti–Scl-70 antibodies: Directed against topoisomerase I and associated with diffuse scleroderma.
· Anticentromere antibodies: Directed against 70/13-kDa proteins that make up the centromere complex and associated with limited scleroderma. This is the discretely speckled pattern on the ANA test.
· Anti–Jo-1 antibodies: Directed against histidyl tRNA synthetase and associated with myositis with interstitial lung disease, arthritis, and mechanic’s hands (known as the antisynthetase syndrome).
· Table 33-1 presents an overview of the various autoantibodies and their disease associations.3
TABLE 33-1 Autoantibodies and Disease Associations
C, centromere; H, homogenous or diffuse; P, peripheral or rim; N, nucleolar; S, speckled.
Data from Klippel JH, ed. Primer on the Rheumatic Diseases, 12th ed. Atlanta, GA: Arthritis Foundation; 2001.
Synovial Fluid Evaluation
· Obtaining synovial fluid from a patient with undiagnosed arthritis, particularly monoarticular arthritis, can be very beneficial.
· The synovial fluid is often characterized by number of cells (especially polymorphonuclear leukocytes [PMNs]), viscosity, and color.
· A Gram stain plus culture and the presence or absence of crystals can confirm the diagnosis (Table 33-2).
TABLE 33-2 Classification of Synovial Fluid
Imaging
· Radiographic changes are common, even in early forms of arthritis.
· The distribution, appearance, severity, and other features of the radiography can help limit the differential diagnosis (Table 33-3).
TABLE 33-3 Radiographic Changes by Disease
CMC, carpometacarpal; DIP, distal interphalangeal; MCP, metacarpophalangeal; MTP, metatarsophalangeal; OA, osteoarthritis; PIP, proximal interphalangeal; SI, sacroiliac.
Osteoarthritis
GENERAL PRINCIPLES
· The typical joints involved in primary OA are lower cervical spine, lower lumbar spine, first carpometacarpal joint of the thumb, proximal interphalangeal joints (Bouchard nodes), distal interphalangeal (DIP) joints (Heberden nodes), hip, knee, and first MTP joint.
· Primary OA is rarely seen in the following locations and, if present here, should raise the suspicion for secondary causes (trauma, inflammatory arthritis, etc.): metacarpophalangeal joints, shoulders, elbows, wrists, and ankles.
DIAGNOSIS
· History consists of mechanical pain (i.e., pain that is worse with activity and relieved with rest). Morning stiffness may be present, but usually lasts for <30 to 60 minutes.
· Examination reveals reduced range of motion, mild swelling, and bony hypertrophy. Small-to-moderate effusions may be present in the knee. Crepitus may be observed with range-of-motion examination.
· Laboratory tests are noncontributory except to rule out other causes of arthritis. Synovial fluid if drawn tends to have <2,000 cells/mm3.
· Radiographic findings are indicated in Table 33-3.
TREATMENT
Guidelines for the treatment of OA have been published by the American College of Rheumatology (ACR).4
Medications
· Acetaminophen at doses of 1,000 mg tid is often helpful and may be as beneficial as nonsteroidal anti-inflammatory drugs (NSAIDs) for some patients. Maximum total daily dose should not exceed 2,000 mg in those with significant liver disease.
· NSAIDs including those that are selective inhibitors of cyclooxygenase-2 (COX-2) are commonly prescribed and have been specifically demonstrated to relieve the signs and symptoms of OA. Patients may require a trial of several of these agents to find the most efficacious. Major toxicities include but are not limited to the following:
o Gastrointestinal (GI) toxicity particularly if certain risk factors are present (e.g., age ≥65, oral steroids/anticoagulant use, and history of ulcer disease/GI bleeding).3 The use of celecoxib or a proton pump inhibitor (PPI) along with a nonselective NSAID may dramatically reduce this risk.5
o Nephrotoxicity and nephrogenic sodium retention.
o Cardiovascular risks. Recent placebo-controlled trials have demonstrated an increased risk of thrombotic cardiovascular events such as myocardial infarction (MI) and strokes with COX-2 selective NSAIDs.6 It is likely that this cardiovascular risk extends to all NSAIDs.
· Topical capsaicin, diclofenac, and lidocaine can improve symptoms particularly if few joints are involved.
· Analgesics such as tramadol and opiates are sometimes indicated. With chronic opiate use, tolerance typically develops, requiring progressively higher doses.
Joint Injections
Intra-Articular Steroids
· Intra-articular steroids have been used for the treatment of OA since the 1950s and are routinely performed by general practitioners. Their use should be limited to those with training in the procedure.
· Available steroid preparations include triamcinolone hexacetonide (fluorinated), triamcinolone acetonide (fluorinated), methylprednisolone acetate (nonfluorinated), and dexamethasone.
· Dose varies based on location, and no controlled studies exist to guide therapy. General guidelines are as follows:
o Large joint (knee and shoulder), 40 to 80 mg (1 to 2 mL)
o Medium joint (wrist, ankle, elbow), 30 mg
o Small spaces (metacarpophalangeal and proximal interphalangeal joints, tendon sheaths), 10 mg
· Precautions:
o Do not inject through cellulitis or psoriatic skin lesion.
o Do not inject the same joint more than three to four times a year.
o Infections can occur but are rare, occurring in only 6 of >100,000 procedures in one classic series.7
o Steroid-induced crystalline arthritis can occur because the steroid preparations involve crystalline glucocorticoid. The reactions usually occur within 24 hours after injection and last 2 to 3 days similar to gout, while septic arthritis from an injection tends to occur >48 hours after the injection.
Hyaluronic Acid Analog Injections
· The most commonly used preparation is hylan G-F 20, which can be given as a single injection that is administered once every 6 months.
· Early studies have shown efficacy equal to naproxen in the treatment of OA, but a large meta-analysis of several studies showed little benefit.8 It is possible that a subset of patients may benefit, and this therapy can be considered in patients with early disease.
· Iatrogenic joint infection, postinjection inflammation (pseudoseptic reaction), and aspiration-proven pseudogout can complicate hyaluronate injections.
Nonpharmacologic Measures
· Nonpharmacologic measures include weight loss, use of a cane or walker, braces and other orthotics, and acupuncture.
· Exercise with and without formal physical therapy. Muscle strength surrounding an affected joint can help stabilize the joint, relieve pain, and possibly reduce progression of joint space narrowing.
Surgery
· Orthopedic consultation for joint replacement of hip, knee, or shoulder should be considered for patients who have exhausted conservative options.
· The timing of surgery is a complicated decision but is primarily based on the severity of the patient’s symptoms.
Rheumatoid Arthritis
GENERAL PRINCIPLES
· RA, the prototypical inflammatory arthritis, affects approximately 1% of the population and accounts for a significant degree of morbidity in affected patients.
· RA is a chronic, polyarticular inflammatory arthritis with a symmetric distribution that affects the hands and feet.
· The etiology is still not well understood, but identification and characterization of biologic mediators of the inflammatory response associated with RA has led to the development of new treatments.9
DIAGNOSIS
The ACR has specified criteria associated with RA (Table 33-4).10 These criteria help outline the symptoms at presentation, but all may not be present in the early course of the disease.
TABLE 33-4 ACR 2010 Criteria for the Classification of Acute Rheumatoid Arthritis
Modified from Aletaha D, Negoit T, Silman AJ, et al. Ann Rheum Dis 2010;69:1580–1588.
Extra-Articular Manifestations
· Pulmonary: RA can cause several types of pulmonary disease such as isolated rheumatoid lung nodules, pleural effusions, or interstitial lung disease, which can progress to fibrosis.
· Felty syndrome is a syndrome of seropositive RA, neutropenia, and splenomegaly. It usually occurs in patients with long-standing severe disease and can result in increased risk of infection.
· Ocular: Severe ocular dryness (keratoconjunctivitis sicca) is the most common ocular problem. Scleritis with a painful red eye that may lead to a thinning of the sclera indicates severe refractory disease and often requires aggressive treatment both systemically and topically.
· Vasculitis: Rheumatoid vasculitis can affect any blood vessel, but the most common manifestation is distal arteritis ranging from nail fold infarcts to gangrene of the fingertips.
· Cardiovascular risk: Chronic inflammation may play a role in the pathophysiology of atherosclerosis. Patients with chronic inflammatory conditions have been shown to be at increased risk of macrovascular complications such as stroke and MI. Indeed, the same is true for RA, and aggressive therapy to reduce cardiovascular risks is an important aspect of RA management.11
Diagnostic Testing
Laboratories
· Refer to Approach to the Patient with Painful Joints above regarding RF, ACPA, ESR, and CRP.
· Complete blood count (CBC), CMP, and hepatitis panel (to rule out hepatitis C as a cause of a positive RF and arthralgias as well as to avoid using hepatotoxic medications in patients with chronic viral hepatitis) should also be performed.
Imaging
· Classical findings on plain radiography include soft tissue swelling, joint space loss, periarticular osteoporosis, and erosions (which eventually develop in the large majority of patients). Musculoskeletal ultrasound can be useful in demonstrating synovial proliferation and inflammation prior to radiographic abnormalities.
· Baseline chest radiography is warranted given the possibility of pulmonary involvement.
TREATMENT
Many aspects of RA diagnosis and treatment can be managed in the primary care setting including establishing the diagnosis early, documenting baseline activity, educating patients, initiating NSAID therapy, referral for physical/occupational therapy, and prescribing disease-modifying therapy within 3 months of diagnosis (e.g., corticosteroids, hydroxychloroquine, sulfasalazine, or methotrexate [MTX]). Patients should be reassessed frequently and referred to a rheumatologist if the response is inadequate.12 Early treatment with disease-modifying antirheumatic drugs (DMARDs) has the potential to retard the progression of disease.
Medications
Most patients with RA benefit symptomatically from the use of NSAIDs, but they do not prevent the progression of bone and cartilage damage.
Glucocorticoids
· Glucocorticoids (especially prednisone) in low doses are extremely effective for promptly reducing the symptoms of RA and can be considered to help patients recover their previous functional status.
· Unfortunately, short courses of oral corticosteroids produce only interim benefit and chronic therapy is often required to manage symptoms and prevent progression of disease.
· Corticosteroids are particularly helpful in treating patients with severe functional impairment or while awaiting clinical response from a slow-acting DMARD.
· Side effects of corticosteroids are many and include hyperglycemia, adrenal insufficiency, osteopenia, and avascular necrosis. If a dose equivalent to 5 mg or greater of prednisone is to be used for longer than 3 months, then a bisphosphonate should be used to prevent bone loss in the absence of contraindications.13
· Intra-articular steroids are particularly useful in patients with a flare of RA in a monoarticular or oligoarticular pattern.
Hydroxychloroquine
· Hydroxychloroquine is indicated for mild-to-moderate RA.
· It is effective at doses of 400 mg PO daily not to exceed 6 mg/kg but is contraindicated in patients with renal or hepatic insufficiency.
· The side effect of macular toxicity is extremely unusual at these doses and rarely occurs before 5 years of treatment. Nonetheless, an ophthalmologist should perform a baseline examination and monitor the patient at least annually.
Sulfasalazine
· Sulfasalazine is also indicated for mild-to-moderate RA and in those who are poor candidates for methotrexate therapy.
· It should be initiated at 500 mg PO bid and gradually increased to 1,000 to 1,500 mg PO bid.
· GI intolerance is common and may be reduced with an enteric-coated preparation.
· It is contraindicated in those allergic to sulfa antibiotics and those with glucose-6-phosphate dehydrogenase deficiency. Severe/fatal skin reactions have occurred.
· Monitoring of liver tests and blood counts is required.
Methotrexate
· MTX is generally considered to be the DMARD of choice for most RA patients. The usual maintenance dose is 7.5 to 20 mg/week orally.
· If MTX is at least partially effective, it should be continued as other agents are added.
· Common side effects include stomatitis, nausea, diarrhea, and thinning of the hair. It is teratogenic.
· Supplementation with folic acid at doses of 1 to 3 mg PO daily can reduce side effects, although efficacy may be somewhat attenuated.
· Serious adverse reactions include hepatotoxicity, lung toxicity, and bone marrow suppression.
· MTX should only be prescribed by those experienced in its use, and careful monitoring of liver tests, serum creatinine, and blood counts is required. It should be used with great caution in the elderly and those with reduced renal function.
Leflunomide
· Leflunomide is a pyrimidine synthesis inhibitor that has been shown to have efficacy comparable to that of MTX in the treatment of RA and may be used in combination with MTX.
· Common side effects include diarrhea, rash, and alopecia. It is teratogenic.
· Monitoring of liver tests and blood counts is required due to the risk of hepatotoxicity and bone marrow suppression. Leflunomide should only be prescribed by those experienced in its use.
Tofacitinib
· Tofacitinib is a small molecule inhibitor of JAK2, a kinase that operates downstream of multiple cytokines and growth factors. Tofacitinib has shown similar efficacy to methotrexate and adalimumab and has been effective in patients who have failed other therapies.
· Side effects include headache, nausea, vomiting, and diarrhea. Elevated cholesterol and transaminase levels as well as neutropenia can occur.
· Tofacitinib requires regular monitoring of blood counts, liver enzymes, and cholesterol. Tofacitinib should only be prescribed by those experienced in its use.
Biologic DMARDs
· Etanercept (Enbrel) is a human fusion protein consisting of both the soluble tumor necrosis factor receptor and the Fc component of IgG.
· Infliximab (Remicade), adalimumab (Humira), golimumab (Simponi), and certolizumab (Cimzia) are monoclonal antibodies against TNF-α.
· Anakinra (Kineret) is a recombinant interleukin-1 (IL-1) receptor antagonist.
· Abatacept (Orencia) is a selective costimulation modulator (inhibitor) and a fusion protein consisting of an IgG Fc fused to the CTLA4 extracellular domain. Studies have shown it to be efficacious in patients who have failed prior treatment with anti-TNF therapy.14
· Rituximab (Rituxan) is a chimeric monoclonal antibody against CD20 and results in the destruction of B cells. This agent has been shown to be efficacious in patients with inadequate responses to TNF inhibitors.15
· Tocilizumab (Actemra) is a monoclonal antibody against the interleukin-6 (IL-6) receptor.
· Consideration of biologic DMARDs is appropriate for patients unresponsive to oral DMARDs.
· Toxicities of the biologic DMARDs include opportunistic infections, disseminated TB, drug-induced lupus, worsened heart failure, demyelinating syndromes, colon perforation, and possibly increased risk of lymphoma.
Combination Therapy
· Combination regimens of multiple DMARDs or DMARDs plus biologic agents may be particularly effective in RA.9 Such combined therapy should only be done in conjunction with a rheumatologist.
· Data show that virtually all DMARDs and biologic DMARDs are more effective when combined with MTX.
Other Nonpharmacologic Therapies
· Occupational therapy usually focuses on the hand and wrist and can help patients with splinting, work simplification, activities of daily living, and assistive devices.
· Physical therapy assists in stretching and strengthening exercises for large joints such as the shoulder and knee, gait evaluation, and fitting with crutches and canes.
· Moderate exercise is appropriate for all patients and can help to reduce stiffness and maintain joint range of motion.
· In general, an exercise program should not produce pain for >2 hours after its completion.
Surgical Management
Orthopedic surgery to correct hand deformities and replace large joints such as the hip, knee, and shoulder should also be considered when pain cannot be controlled adequately with medications.
Infectious Arthritis and Septic Bursitis
GENERAL PRINCIPLES
· Infectious arthritis is generally categorized into gonococcal and nongonococcal infection.
· The usual presentation is with fever and acute monoarticular arthritis, although multiple joints may be affected by hematogenous spread of pathogens.
· Nongonococcal infectious arthritis in adults tends to occur in patients with previous joint damage or compromised host defenses.
o Nongonococcal septic arthritis is caused most often by Staphylococcus aureus (60%) and Streptococcus spp.
o Gram-negative organisms are less common, except with IV drug abuse, neutropenia, concomitant urinary tract infection, and prosthetic joints.
· Gonococcal arthritis is more common than nongonococcal septic arthritis and is the most common cause of monoarticular arthritis in patients between the ages of 20 and 30.16 The clinical spectrum of disease often includes migratory or additive polyarthralgias, followed by tenosynovitis or arthritis of the wrist, ankle, or knee, and asymptomatic dermatitis on the extremities or trunk.
· Nonbacterial infectious arthritis is common with many viral infections, especially hepatitis B, rubella, mumps, infectious mononucleosis, parvovirus, enterovirus, adenovirus, and HIV. Hepatitis C infection is associated with the formation of cryoglobulinemia, which can present as a polyarticular inflammatory arthritis with glomerulonephritis, cutaneous vasculitis, and mononeuritis multiplex.
· Septic bursitis, usually involving the olecranon or prepatellar bursa, can be differentiated from septic arthritis by localized, fluctuant superficial swelling with relatively painless joint motion (particularly extension). Most patients have a history of previous trauma to the area or an occupational predisposition (e.g., so-called housemaid’s knee and writer’s elbow). Staphylococcus aureus is the most common pathogen.
DIAGNOSIS
· Joint fluid examination, including Gram stain of a centrifuged pellet, and culture are mandatory to make a diagnosis and to guide management.
· A joint fluid leukocyte count is useful diagnostically and as a baseline for serial studies to evaluate response to treatment.
· Cultures of blood and other possible extra-articular sites of infection also should be obtained.
· In contrast to nongonococcal septic arthritis, Gram staining of synovial fluid and cultures of blood or synovial fluid are often negative in gonococcal arthritis.
TREATMENT
· Hospitalization is indicated to ensure drug compliance and careful monitoring of the clinical response.
· IV antimicrobials provide good serum and synovial fluid drug concentrations. Oral antimicrobials are not appropriate as initial therapy, and there is no role for intra-articular antibiotic therapy.
· Arthrocenteses should be performed daily or as often as necessary to prevent reaccumulation of fluid and monitor response to therapy.
· General supportive measures include splinting of the joint, which may help to relieve pain. However, prolonged immobilization can result in joint stiffness.
Medications
· An NSAID or selective COX-2 inhibitor is often useful to reduce pain and to increase joint mobility but should not be used until response to antimicrobial therapy has been demonstrated by symptomatic and laboratory improvement.
· Initial therapy is based on the clinical situation and a carefully performed Gram stain, which reveals the organism in approximately 50% of patients.17
o With a positive Gram stain, antibiotic coverage can be adjusted accordingly.
o With a nondiagnostic Gram stain, antibiotics should be selected to cover S. aureus, Streptococcus spp., and Neisseria gonorrhoeae in otherwise healthy patients, whereas broad-spectrum antibiotics are appropriate in immunosuppressed patients.
o IV antimicrobials are usually given for at least 2 weeks, followed by 1 to 2 weeks of oral antimicrobials, with the course of therapy tailored to the patient’s response. Infectious disease consultation can be helpful for treatment.
· Treatment for gonococcal arthritis begins with an intravenous antibiotic for the first 1 to 3 days, generally ceftriaxone, 1 g daily or ceftizoxime, 1 g every 8 hours.
o Response to IV antibiotics is usually noted within the first 24 to 36 hours of treatment.
o After initial clinical improvement, therapy is continued with an oral antibiotic to complete 7 to 10 days of treatment.
o Ciprofloxacin, 500 mg bid, or amoxicillin/clavulanate, 500/875 mg bid, can be used, although resistance to fluoroquinolones is increasing and decisions regarding treatment should be based on regional guidelines.18
· Viral arthritides are generally self-limited, lasting for <6 weeks, and respond well to a conservative regimen of rest and NSAIDs.
· Septic bursitis should be treated with aspiration, which should be repeated if fluid reaccumulates. Oral antibiotics and outpatient management are usually appropriate, and surgical drainage is rarely indicated.
Surgical Management
Surgical drainage or arthroscopic lavage and drainage are indicated in the following circumstances:
· A septic hip that cannot easily be accessed by arthrocentesis
· Joints in which the anatomy, large amounts of tissue debris, or loculation of pus prevent adequate needle drainage
· Septic arthritis with coexistent osteomyelitis
· Joints that do not respond in 4 to 6 days to appropriate therapy and repeated arthrocenteses
· Prosthetic joint infection
Gout
GENERAL PRINCIPLES
· Deposition of microcrystals in joints and periarticular tissues results in gout, pseudogout, and basic calcium phosphate (BCP) disease.19
· Gout is caused by the accumulation of excess amounts of uric acid in the body, leading to deposition of monosodium urate crystals when levels exceed solubility.
· Gout can produce four distinct clinical syndromes: acute gouty arthritis, chronic tophaceous gout, urate nephropathy, and urate nephrolithiasis.
· All complications of gout result from hyperuricemia. In 90% of cases, this occurs as a result of underexcretion of urate.
· Risk factors include male sex, hypertension, hyperlipidemia, obesity, renal dysfunction, alcohol, dehydration, and drugs (e.g., low-dose salicylates, diuretics, ethambutol, pyrazinamide, levodopa, cyclosporine, and tacrolimus).20
DIAGNOSIS
Clinical Presentation
· Acute gouty arthritis presents with acute pain and swelling, usually of a single joint.
· Commonly affected joints include the great toe MTP joint (i.e., podagra), ankle, knee, and wrist.
· Episodes often occur at night and frequently accompany acute medical illnesses, postsurgical periods, dehydration, fasting, or heavy alcohol consumption.
· Pain is severe, and immediate medical attention to provide pain relief is essential.
· Periarticular involvement is rare at presentation but may occur in long-standing cases.
· Intense periarticular inflammation with desquamation of skin may give the appearance of cellulitis.
Diagnostic Testing
· Gout is diagnosed by polarized microscopy of synovial fluid demonstrating bright, negatively birefringent, needle-shaped crystals (often found within a PMN).
· Cell counts of synovial aspirates are usually consistent with an inflammatory arthritis (white cells in the tens of thousands, mostly PMNs).
· Aspiration of superficial tophi with a 25-gauge needle can also provide diagnostic material.
TREATMENT
NSAIDs
· NSAIDs are particularly effective and are the treatment of choice for acute gout.
· They should be started in maximal doses and tapered over several days once the gouty flare has subsided.
· A common high-dose NSAID regimen is indomethacin 50 mg PO qid given for several days until relief is obtained, followed by 50 mg tid for 2 to 3 days, 50 mg bid for 2 to 3 days, 50 mg/day for a few days, and then discontinue.
· Naproxen, ibuprofen, sulindac, and other NSAIDs are also effective and are generally better tolerated than high-dose indomethacin.
Colchicine
· The current approved dose of colchicine for acute gout is 1.2 mg PO then 0.6 mg 1 hour later as needed. Avoid this treatment in patients on colchicine prophylaxis and taking a CYP3A4 inhibitor. Dose adjustment is not needed for renal impairment but should not be repeated for 2 weeks. For patients on hemodialysis, only 0.6 mg should be given and not repeated.
· The traditional dose of colchicine every hour is obsolete and should not be used.
· IV colchicine is no longer available.
Glucocorticoids
· Oral steroids can be used when other therapies are contraindicated. Prednisone initiated at 60 mg/day and tapered rapidly can provide adequate symptomatic relief while avoiding toxicities of long-term steroid use.
· Intra-articular aspiration and corticosteroid injection is appropriate for large joints and is an excellent choice for patients who are not good candidates for NSAIDs. Because the knee joint often has a tense effusion, aspiration of as much fluid as possible can bring immediate relief, followed by injection of 1 to 2 mL corticosteroid with an equal volume of 1% lidocaine. A volume of 1 mL is appropriate for the ankle.
Biologic Therapy
Pegloticase (Krystexxa) is a pegylated, recombinant uricase that can be administered to patients with chronic tophaceous gout who have had persistent disease and elevated uric acid despite maximum therapy with other uric acid–lowering medications. Patients must be tested for glucose-6-phosphate dehydrogenase deficiency prior to administration. Pegloticase should only be prescribed by those experienced in its use.
Prophylactic Treatment
· Prophylactic treatment is advisable when patients have recurrent attacks several times per year.
· Colchicine, 0.6 mg once or twice daily, may be used (dose must be reduced for renal insufficiency or concomitant CYP3A4 inhibitors). Low-dose NSAIDs such as indomethacin, 25 mg bid, or naproxen, 250 mg bid, are another option. In patients with multiple recurrent attacks, uric acid–lowering therapy may be beneficial.
· Xanthine oxidase inhibitors (allopurinol and febuxostat) reduce uric acid production and are much easier to administer than probenecid.
o Xanthine oxidase inhibitors are indicated for recurrent attacks that are not controlled with colchicine or NSAIDs.
o Other indications for xanthine oxidase inhibitors include the presence of tophi, renal stones, and severe hyperuricemia (>13 mg/dL).
o Asymptomatic hyperuricemia should not be treated with these medications.
o A starting dose of allopurinol 100 mg/day can be increased after 2 to 4 weeks to 300 mg/day. Sometimes, higher doses (400 to 600 mg/day) are required. In the setting of renal impairment, starting dose should be 50 mg. The correct dose is that which reduces the serum uric acid to <6 mg/dL.
o Febuxostat should be started at 40 mg daily and may be increased to 80 mg daily if necessary. There are no data for higher doses or for use in patients with creatinine clearance <30.
o Xanthine oxidase inhibitors should not be started during an acute attack as they may cause a severe flare of the disease. Administration of prophylactic colchicine or low-dose NSAIDs before initiation of uric acid–lowering therapy may prevent the gouty attacks that sometimes accompany the initiation of allopurinol treatment. It is not necessary to discontinue use of a urate-lowering medication if a gout attack occurs after it is started.
o These medications are usually well tolerated, although a severe hypersensitivity syndrome can occur, especially with renal insufficiency and diuretic use.
· Probenecid prevents tubular reabsorption of uric acid and can be used to enhance urinary excretion of uric acid provided that the baseline 24-hour urinary uric acid is 600 mg or less.
o If the 24-hour uric acid is >600 mg, increasing the urinary excretion of uric acid may precipitate uric acid kidney stones.
o Probenecid can be initiated at 500 mg PO daily and increased as needed, not exceeding 3,000 mg in three divided doses.
o Normal renal function is necessary for probenecid to be effective.
o Salicylates at any dose antagonize the effect of probenecid.
· A 12-year study of 730 patients with gout suggested that high levels of meat and seafood in the diet are associated with an increased risk of gout, whereas dairy products may be protective. The level of purine-rich vegetables and total protein intake was not associated with an increased risk of gout.21
Pseudogout
· Pseudogout is caused by deposition of calcium pyrophosphate crystals and tends to occur more often in elderly individuals.
· It may be precipitated by surgery and has been associated with hypothyroidism, hyperparathyroidism, diabetes, and hemochromatosis.
· Like gout, pseudogout tends to cause monoarticular attacks, especially in large joints.
· Symmetric involvement of the hands may mimic RA.
· Periarticular inflammation can be severe, mimicking cellulitis.
· Polarized microscopy of synovial fluid reveals rhomboid-shaped crystals that are positively birefringent.
· Radiographic studies may demonstrate chondrocalcinosis (especially knee, wrist, and symphysis pubis) but alone are not diagnostic of pseudogout.
· Treatment is the same as for gout, except that there is no role for uric acid–lowering therapy. Joint aspiration, alone or with steroid injection, often provides immediate relief of pain.
Apatite Deposition Disease
· Apatite deposition disease may present with periarthritis or tendonitis, particularly in the elderly and in patients with chronic renal failure.
· An episodic oligoarthritis may also occur, and apatite disease should be suspected when no crystals are present in the synovial fluid.
· Erosive arthritis may be seen, particularly in the shoulder (e.g., Milwaukee shoulder, a syndrome of large shoulder effusion, rotator cuff pathology, and the presence of basic calcium phosphate [BCP] crystals in synovial fluid).
· Hydroxyapatite complexes and BCP complexes can be identified only by electron microscopy, mass spectroscopy, or alizarin red staining, none of which are readily available to the clinician.
· The treatment of apatite disease is similar to that for pseudogout, except that recent studies suggest that early intervention and washing out the joint may help prevent progression of the disease.22
· Referral to orthopedic surgery may be required.
Systemic Lupus Erythematosus
GENERAL PRINCIPLES
· SLE is a multisystem autoimmune disease of unknown etiology that commonly occurs in women of childbearing age. There is clearly a genetic predisposition.
· Manifestations of SLE are protean, and organ systems involved may include skin, heart, lungs, nervous system, kidneys, hematopoietic system, and joints.
· African-Americans and Hispanics have a worse prognosis.
· SLE can occur in the elderly, but when it does, it is usually milder.
DIAGNOSIS
Clinical Presentation
· The ACR has proposed 11 criteria for the diagnosis of SLE (Table 33-5).23
· For inclusion in clinical studies, a diagnosis requires that at least four of them be present at some point through the course of the disease. These criteria may be used to aid in the clinical diagnosis of lupus, recognizing that having four criteria in isolation is neither necessary nor sufficient for the diagnosis.23
TABLE 33-5 Systemic Lupus Erythematosus Classification Criteria Definitions
dsDNA, double-stranded (native) deoxyribonucleic acid; Sm, Smith nuclear antigen.
Modified from Tan EM, Cohen AS, Fries JF, et al. Arthritis Rheum 1982;25:1271–1277.
Diagnostic Testing
· The ANA is highly sensitive and is positive in virtually all patients with SLE. Therefore, a negative ANA is useful to exclude SLE; however, a positive ANA test alone is of little significance in the absence of clinical evidence of disease, regardless of how high the titer.
· Antibodies to double-stranded DNA are very specific for SLE, especially when present at high titers.
· High levels of anti-DNA antibody can correlate with disease activity, especially with lupus nephritis. Therefore, quantitative anti-DNA titers are sometimes useful in monitoring disease flares and response to treatment. However, lupus often occurs in the absence of anti-DNA antibodies.
· Anti-Sm is very specific for SLE although it is positive in a minority of patients.
· Serum complement measures, C3 and C4, are sometimes abnormal in active SLE, especially in the setting of nephritis, and may rise and fall with disease activity.
· Antiphospholipid antibodies are important in diagnosing the antiphospholipid syndrome (APS), characterized by fetal loss, venous and arterial thromboses, CNS events, and thrombocytopenia.24
o Diagnosis of APS is relevant, as the treatment may necessitate lifelong anticoagulation.
o Anticardiolipin and beta2-glycoprotein-I antibodies are measured by ELISA. IgG antibodies in significant titer are more predictive of clinical events than are IgM or IgA.
o False-positive Venereal Disease Research Laboratory test (VDRL) or rapid plasma reagin (RPR) can be caused by the presence of APA reacting with the cardiolipin substrate. The fluorescent treponemal antibody absorption test should be negative, although a low-titer beaded pattern is sometimes observed.
o The lupus “anticoagulant” (LAC) is not specific for lupus and despite its name promotes coagulation. The activated thromboplastin time (PTT) assay does not correct with the addition of normal plasma, but does correct when phospholipid is added in excess to neutralize the APA. The dilute Russell Viper venom time (dRVVT) is another test for LAC that does not require a prolonged PTT.
o A positive LAC or high-titer IgG anticardiolipin antibody is more predictive of clinical events than the other tests.
TREATMENT
· Treatment for SLE is dependent on the clinical scenario.
· For patients without life- or organ-threatening disease, initiation of conservative therapy is appropriate: sunscreen and sun avoidance, topical steroids for isolated skin lesions, and hydroxychloroquine for arthralgias and fatigue.
· More severe cases of SLE may require more aggressive therapy. In general, prednisone in moderate (15 to 30 mg/day) or higher (40 to 60 mg/day) doses is usually the first-line therapy for a moderate-to-severe lupus flare. Steroid-sparing therapies are frequently needed when flares are recurrent. Such therapies include:
o Mycophenolate mofetil.
o Azathioprine.
o Methotrexate or leflunomide.
o Cyclophosphamide for life-threatening disease.
o Belimumab, a monoclonal antibody that inhibits B-cell–activating factor.
o B-cell depletion with rituximab is widely thought to benefit a subset of patients with SLE although randomized clinical trials have yet to confirm this.
o Immunoablation with or without stem cell transplantation for refractory disease is still considered to be an investigational approach.
Symptom-Specific Treatments
· Arthritis often responds to NSAIDs, although they must be used with caution in patients with decreased renal function. The addition of prednisone in low doses (5 to 10 mg/day) may be necessary. Long-term treatment with hydroxychloroquine or MTX helps control arthritis (see the “Rheumatoid Arthritis” section).
· Rashes may respond to topical corticosteroids (fluorinated topical steroids on the face should be avoided because of the risk of subcutaneous atrophy). If topical agents are not effective, systemic corticosteroids may be needed. Hydroxychloroquine is often beneficial in the long-term management of rash and may help to reduce the need for corticosteroids.
· Oral ulcers can be treated with dental paste that contains benzocaine (Orabase B) or triamcinolone (Kenalog in Orabase) or an over-the-counter anesthetic oral rinse (e.g., Ulcer Ease).
· Mild cases of pleuritis and pericarditis sometimes respond to NSAIDs, whereas more severe cases require corticosteroids.
· The treatment of renal disease is complicated.25
o For most serious renal lesions, periodic monthly cyclophosphamide has traditionally been administered, although MMF is being used more frequently as first-line therapy.
o High doses of corticosteroids, administered either orally or intravenously, are also commonly used in the acute setting as cyclophosphamide, and mycophenolate mofetil may take weeks to reach peak efficacy.
· For hematologic manifestations, such as hemolytic anemia, severe leukopenia, or thrombocytopenia, corticosteroids in moderate-to-high doses are required.
· Neuropsychiatric disease is difficult to assess because there is no laboratory test or physical finding that can unequivocally support the diagnosis of lupus affecting the central nervous system. The diagnosis is based on clinical factors and is a diagnosis of exclusion. Aggressive treatment with high-dose steroids may be necessary to help control symptoms.
Seronegative Spondyloarthropathies
GENERAL PRINCIPLES
· The spondyloarthropathies are a group of articular disorders characterized by involvement of the axial skeleton with a negative RF.26
· These disorders include ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and arthritis associated with inflammatory bowel disease.
· Ankylosing spondylitis, the prototype of the spondyloarthropathies, is diagnosed in men much more commonly than in women, partly because the spine symptoms in women tend to be more subtle. Associated acute iritis produces severe eye pain and blurred vision and requires urgent referral to an ophthalmologist.
· Reactive arthritis occurs after infectious syndromes such as nongonococcal urethritis or infectious diarrhea with Shigella spp., Salmonella spp., or Yersinia enterocolitica. A reactive arthritis syndrome of urethritis, arthritis, and conjunctivitis was previously referred to as Reiter syndrome.
· Psoriatic arthritis has five basic presentations: spinal predominance, polyarticular small joint involvement, oligoarticular asymmetric large joint involvement, DIP joint predominance, and the rare arthritis mutilans with telescoping digits. In general, the severity of joint disease does not parallel that of the skin disease, except for the DIP pattern, which correlates with nail abnormalities.
· Ulcerative colitis and Crohn disease may be accompanied by inflammatory arthritis of two types. The peripheral joint variety tends to parallel the activity of the bowel disease, whereas the spondylotic pattern typically has an independent course of the bowel disease.
· Axial spondyloarthropathy is a relatively new term that includes patients with axial-predominant spondyloarthropathy with and without radiographic evidence of sacroiliitis.
DIAGNOSIS
Clinical Presentation
History
· The characteristic history is that of inflammatory back pain. Five distinguishing symptoms include gradual onset, onset before the age of 40 years, morning stiffness, improvement with mild exercise, and duration >3 months.
· When peripheral joint involvement is present, it is typically asymmetric and oligoarticular, generally in the lower extremities.
· Inflammation generally occurs where tendons insert on bone (enthesopathy) and produces so-called sausage digits of individual fingers and toes (dactylitis), plantar fasciitis, and Achilles tendonitis.
· Nonarticular symptoms may include aphthous stomatitis, ocular inflammation such as conjunctivitis and iritis, and aortic dilatation.
Physical Examination
· Spine motion may be simply assessed by having the patient bend forward with the knees extended and measuring the distance between the fingertips and floor (recognizing that hamstring tightness reduces the range of motion). To perform the modified Schober test, mark two points 10 cm cephalad to and 5 cm caudal to the sacral dimples of Venus. With forward flexion, the line between these points should increase by at least 5 cm.
· Peripheral joints should be checked for diffuse fusiform swelling of fingers and toes (sausage digits or dactylitis) and asymmetric swelling of large joints, especially the knees and ankles.
· Ocular findings in ankylosing spondylitis and reactive arthritis include redness and a pupil that reacts asymmetrically, indicating previous episodes of ocular inflammation resulting in synechiae.
· Skin findings in psoriasis are usually obvious, but the following areas should be specifically examined to look for subtle changes: the scalp, external auditory canal, umbilicus, and intergluteal cleft. It may be difficult to distinguish the skin findings of reactive arthritis from those of psoriasis.
Diagnostic Testing
· The RF is by definition negative, and the ESR is inconsistently elevated.
· Although the human leukocyte antigen B27 is present in >90% of Caucasians with ankylosing spondylitis, its frequency is lower in other ethnic groups and in other spondyloarthropathies. It is present in approximately 8% to 10% of unaffected Caucasians.
· Radiographs to look for sacroiliitis include an anteroposterior view of the pelvis, sometimes supplemented by modified Ferguson views of the sacroiliac joints (taken with a 30-degree cephalad angle). Definite radiographic changes take years to develop. MRI of the SI joints enables diagnosis of early disease. Radiographs of peripheral joints may show periostitis.
TREATMENT
· Physical therapy to improve and maintain spinal motion is extremely important.
· NSAIDs are the mainstay of symptomatic treatment. High doses are generally required (e.g., indomethacin, 50 mg qid; naproxen, 500 mg tid).
· Sulfasalazine is efficacious in some patients for whom NSAIDs do not provide adequate relief (see the “Rheumatoid Arthritis” section).
· MTX has a well-established role in treating psoriatic arthritis and is sometimes effective for peripheral joint problems in the other spondylotic disorders. Patients with psoriasis have an increased risk of fibrosis and cirrhosis from methotrexate and should undergo liver biopsy at cumulative dose intervals of 2.5 to 3 g.
· The TNF blockers have been shown to be effective in providing symptomatic relief in ankylosing spondylitis and psoriatic arthritis.
Scleroderma
GENERAL PRINCIPLES
· Scleroderma is a poorly understood process that leads to pathologic changes of small-vessel vasculopathy (distinct from vasculitis), fibrosis, and proliferation of myofibroblasts in affected organs. The disease is characterized by fibrosis of the skin and internal organs, especially the lungs, heart, kidneys, and GI tract.
· The two major forms of this disease are (1) diffuse scleroderma and (2) limited scleroderma (known as the CREST syndrome which stands for Calcinosis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasias).
DIAGNOSIS
Clinical Presentation
· The diagnosis of scleroderma rests on the history and physical examination.
· Skin findings on physical examination are key to the diagnosis. Patients with diffuse as well as limited disease may have tight skin on the fingers as well as involvement of facial skin, most often around the mouth. In diffuse disease, the skin proximal to the elbows and knees is involved as well as loss of facial wrinkles and perioral fibrosis.
· Raynaud phenomenon:
o Raynaud phenomenon is present in almost all patients with scleroderma.
o The classic history is one of triphasic skin color change: pallor (vasospasm) followed by cyanosis (desaturation of tissue hemoglobin) followed by rubor (reactive hyperemia). Many patients note only two of these changes.
o Cold temperatures, tobacco smoke, stress, and certain medications may provoke symptoms.
o The nail fold capillaries can be visualized by coating the cuticle with a thin layer of clear surgical lubricant and looking through an ophthalmoscope set at +40. Dilatation or dropout of nail fold capillaries increases the likelihood that Raynaud phenomenon will evolve into a systemic rheumatic disease.27
Diagnostic Testing
· ANA is positive in most patients.
· Anticentromere antibody is a special subset of ANA, with a finely speckled pattern, and is seen in the majority of patients with limited disease.
· Anti–Scl 70 is an antibody to topoisomerase that is quite specific for diffuse disease but is found in a minority of patients. This antibody is associated with interstitial lung disease and scleroderma renal crisis.
TREATMENT
· Treatment is largely supportive and organ system specific because there is no treatment that clearly alters the long-term course of this disease.
· The most important aspect of treatment of Raynaud phenomenon is protecting the hands from cold temperatures. Covering the head during cold weather is essential, because much of core body heat can be lost through the head, leading to lower body temperature in the extremities.
o A variety of vasodilating calcium channel blockers (especially dihydropyridines such as nifedipine or amlodipine) help reduce recurrence and severity of symptoms.
o Sildenafil and bosentan are not FDA approved for this indication, but may be effective in refractory cases.28
· Azotemia, proteinuria, and a microangiopathic hemolytic anemia can develop in patients with scleroderma renal crisis. Hypertension must be managed aggressively, and the angiotensin-converting enzyme (ACE) inhibitors are the drugs of choice for scleroderma renal crisis. Data presented at the American College of Rheumatology call into question the use of ACE inhibitors prior to development of scleroderma renal crisis. The use of ACE inhibitors has decreased the mortality due to renal crisis such that pulmonary disease is now the leading cause of death in these patients.
· GI complications:
o Gastroesophageal reflux can be treated with proton pump inhibitors or high-dose histamine-2 receptor blockers. Surgery to correct reflux should be avoided in these patients because of coexisting motility disorders.
o Esophageal strictures sometimes require mechanical dilatation.
o Malabsorption due to bacterial overgrowth can be treated with broad-spectrum antibiotics.
· Limited data indicate that cyclophosphamide therapy can reduce the progression of interstitial lung disease, and studies are underway to evaluate MMF.29
· Many patients with systemic sclerosis may develop complications of pulmonary hypertension. Recent advances have been made in the treatment of pulmonary hypertension associated with scleroderma. Treatment options include sildenafil, bosentan, and other prostacyclin analogues.30,31
· Coronary artery vasospasm can cause angina that may be responsive to calcium channel blockers.
Sjögren Syndrome
GENERAL PRINCIPLES
Sjögren syndrome is a multisystem autoimmune disease characterized by dysfunction of exocrine glands. It may occur as a primary disorder or secondary to other rheumatic diseases such as RA, SLE, scleroderma, or inflammatory myopathy.
DIAGNOSIS
Clinical Presentation
History
· History is notable for the sicca symptoms of dry eyes and dry mouth.
· Parotid gland swelling may occur, and occasionally, patients have symptoms of pancreatic insufficiency with diarrhea and malabsorption.
· Symptoms of vaginal dryness may be present in women.
Physical Examination
· Eye exam may show a diminished corneal light reflex and reduced tear meniscus.
· Oral examination reveals a diminished or absent sublingual salivary pool, and the tongue and buccal mucosa may appear dry.
· The parotid and submandibular glands are sometimes enlarged.
· Inflammatory arthritis and cutaneous vasculitis may also be associated with Sjögren syndrome.
· Additionally, patients with Sjögren syndrome often have symptoms of Raynaud phenomenon.
· Enlargement of lymph nodes, liver, or spleen raises the suspicion of lymphoma, the incidence of which is increased 40-fold.
Diagnostic Testing
· Laboratory tests associated with Sjögren syndrome include ANA, RF, and SSA (anti-Ro) or SSB (anti-La) antibodies.
· Lymphocytic infiltration on biopsy of minor salivary glands from the inner surface of the lower lip helps support the diagnosis of Sjögren syndrome.
TREATMENT
· Artificial tears are helpful for dry eye symptoms and can be self-administered as needed. Optic cyclosporine has been shown to decrease symptoms of ocular dryness. For more severe cases, an ophthalmologist can accomplish temporary or permanent occlusion of the lacrimal puncta.
· Treatment of dry mouth symptoms is more challenging but important to reduce discomfort and the incidence of dental caries.
o Conservative measures, such as increased oral water intake and chewing sugarless gum, can provide symptomatic relief.
o Oral pilocarpine, 5 mg qid, or cevimeline, 30 mg tid, has been shown to increase saliva production and improve symptoms of oral dryness.
o Various saliva substitutes are available over the counter but may be poorly tolerated.
· Hydroxychloroquine (see the “Rheumatoid Arthritis” section) is sometimes prescribed for various manifestations of Sjögren syndrome.
· Immunosuppressive agents may be required for involvement of major organs including vasculitis.
Vasculitis
GENERAL PRINCIPLES
· The clinical manifestations of vasculitis are protean. Fever, weight loss, mononeuropathy, rash, arthritis, abdominal pain, sinusitis, pulmonary hemorrhage, and glomerulonephritis are among the many presenting symptoms.
· Physical manifestations tend to be nonspecific, but skin lesions such as palpable purpura, livedo reticularis, and digital gangrene raise suspicion for vasculitis.
· Wrist-drop or foot drop is suggestive of mononeuropathy, another important clue to the presence of systemic vasculitis.
DIAGNOSIS
Specific Vasculitic Syndromes
· Polyarteritis nodosa includes many of the above symptoms but typically presents with hypertension, glomerulonephritis, abdominal pain, and mononeuropathy (commonly wrist-drop or foot drop). Onset may be gradual or sudden, and patients are systemically ill.
· Giant cell arteritis (GCA) presents with headache, visual disturbance, tongue and jaw claudication, and scalp tenderness. GCA is often associated with polymyalgia rheumatica (PMR).
· Takayasu arteritis affects the aorta and its branches. It occurs most commonly in young Asian women and is often detected by asymmetric pulses or blood pressure measurements. Other symptoms include headache, arm claudication, visual changes, and arthralgias.
· Granulomatosis with polyangiitis (formerly known as Wegener granulomatosis) presents with the classic triad of upper airway disease (sinusitis), lower airway disease (pulmonary hemorrhage), and glomerulonephritis. Limited granulomatosis with polyangiitis occurs without renal involvement.
· Churg-Strauss vasculitis is classically associated with severe asthma and systemic eosinophilia. Peripheral neuropathy, mononeuritis, and pulmonary and cutaneous involvement are common.
· Cutaneous vasculitis may be common to all subtypes of vasculitis and commonly presents with palpable purpura, usually in dependent areas of the lower extremities. Although often associated with systemic diseases, vasculitis may be limited to the skin.
· Cryoglobulinemia, frequently associated with hepatitis C, can present with purpura, arthritis, and glomerulonephritis.
· Secondary vasculitis: vasculitis may also occur secondary to other rheumatic diseases, such as RA and SLE, and should be suspected when symptoms include cutaneous vasculitis, peripheral neuropathies, or mesenteric ischemia.
Diagnostic Testing
· Laboratory findings are nonspecific, but anemia, elevated ESR, and urinalysis abnormalities (proteinuria, hematuria, and cellular casts) are often seen.
· c-ANCA that represents antibody to proteinase-3 is specific for granulomatosis with polyangiitis.
· Biopsy of affected tissues, such as skin, muscle, artery, and nerve, can be valuable in establishing the diagnosis. The gastrocnemius muscle and sural nerve are common sources of diagnostic material. Renal biopsy findings tend to be nonspecific (crescentic glomerulonephritis with negative immunofluorescence) and rarely include vasculitis.
TREATMENT
· Treatment depends on the specific diagnosis.
· High-dose corticosteroids (prednisone at 1 mg/kg/day) are usually effective, especially in the short term.
· Cyclophosphamide can also be used, in either a daily oral dose of 1 to 2 mg/kg/day or a monthly IV dose of 0.5 to 1 g/m2.
· Rituximab has been shown to be as effective as cyclophosphamide for initial treatment of granulomatosis with polyangiitis.
· Vasculitis that is limited to the skin does not require potent immunosuppressive treatment, and therapies such as methotrexate, azathioprine, or even colchicine may be effective.
Polymyalgia Rheumatica and Giant Cell Arteritis
GENERAL PRINCIPLES
PMR and GCA represent a continuum of disease. A patient may have one or both diagnoses, and they can develop in either order. PMR and GCA occur after the age of 50 years, and the incidence increases with age.
DIAGNOSIS
Clinical Presentation
· The classic history for PMR is morning stiffness, worse in the neck, shoulder, and pelvic girdle region. The patient may complain of the inability to roll over in bed at night.
· GCA presents with headache, tongue or jaw claudication, scalp tenderness, and vision loss (typically amaurosis fugax).
· Systemic symptoms such as fever and weight loss may also occur in GCA.
· Physical examination of patients with PMR is most notable for a profound inability to abduct and elevate the shoulders in most cases. Synovitis, if present, should be minimal. Although an uncommon finding, in GCA, a tender, nodular superficial temporal artery with reduced or absent pulse strongly suggests the diagnosis.
Diagnostic Testing
· Virtually all patients with PMR or GCA have an elevated ESR. The high sensitivity of this test makes PMR/GCA unlikely with a normal ESR. CRP may also be elevated.
· A temporal artery biopsy should be performed in all patients in whom GCA is suspected. The pathologic findings of granulomatous inflammation with giant cells and fragmentation of the internal elastic lamina confirm the diagnosis. Because the temporal artery biopsy does not have 100% sensitivity, when the clinical presentation is convincing, a diagnosis of GCA may be made despite a negative biopsy.
TREATMENT
· Treatment for PMR is focused on relieving discomfort and improving quality of life.
· Although NSAIDs occasionally are effective for PMR, most patients require prednisone in doses of 10 to 15 mg/day for relief.
· Failure of the patient to improve dramatically and rapidly with low-dose corticosteroids should lead to reconsideration of the diagnosis of PMR.
· Treatment can be tapered over approximately 1 year, although some patients require longer treatment.
· GCA must be treated aggressively as a systemic vasculitis.
o For suspicion of GCA, high-dose prednisone must be initiated immediately at approximately 60 mg daily to prevent the complication of irreversible vision loss.
o Treatment should not be delayed until a temporal artery biopsy can be performed, because the diagnostic findings on biopsy can still be demonstrated several days after corticosteroid therapy has been started. Furthermore, patients may develop blindness during the first few days of therapy.
o The dose of prednisone can be tapered slowly over several months, provided that the patient remains asymptomatic.
o Methotrexate may be an effective steroid-sparing agent in some patients, although the evidence is conflicting.
Polymyositis and Dermatomyositis
GENERAL PRINCIPLES
· Polymyositis (PM) and dermatomyositis (DM) are both idiopathic inflammatory myopathies but have many distinctions.
· DM is associated with skin manifestations, but PM is not. Proximal myopathy is characteristic of both, but DM may sometimes occur without myositis.
· There does appear to be an association with malignancy in a minority of patients, more pronounced with DM.
DIAGNOSIS
Clinical Presentation
History
· The cardinal feature of myositis is proximal muscle weakness without pain. Typically, patients notice difficulty in getting out of a car, chair, or bathtub; climbing stairs; or using their arms above the head. Distal muscle strength should be normal except in inclusion body myositis, which tends to occur in older individuals.
· Dysphagia with nasal regurgitation may occur if there is weakness of the striated muscle of the upper esophagus.
· Dyspnea due to interstitial lung disease and joint pain from inflammatory arthritis may occur, especially in the antisynthetase syndrome (PM with anti–Jo-1 antibody).
Physical Examination
· The exam should focus on evidence of proximal muscle weakness, a sensitive test of which is the ability to raise the head from the supine position. Standing up from a chair with the arms folded across the chest and rising from a deep squat are other good tests for proximal weakness.
· Patients with dermatomyositis have typical skin findings such as a heliotrope rash on the eyelids, Gottron papules on the knuckles, and nail fold capillary abnormalities.
· Mechanic’s hands are classically associated with the antisynthetase syndrome.
Diagnostic Testing
· Laboratory studies should include serum muscle enzymes, especially creatine phosphokinase (CK), which is elevated in virtually all cases of inflammatory myopathy. Elevations of aspartate aminotransferase (AST) and aldolase may occur but are less specific for muscle injury.
· Myositis-associated antibodies (such as anti–Jo-1, anti–MI-2, and anti-SRP) are primarily important for classifying diseases in research but sometimes can be helpful in atypical cases.
· Most patients should undergo electromyography (EMG) to look for the classic myopathic findings of fibrillations, positive sharp waves, and low-amplitude polyphasic motor unit potentials.
· Muscle biopsy can be done on the contralateral side, corresponding to the most abnormal area on the EMG. The biceps, deltoid, and vastus medialis are the muscles that are easily biopsied. MRI has recently been shown to help with identifying affected muscles for biopsy.
TREATMENT
· Treatment involves high doses of corticosteroids, either 1 mg/kg/day prednisone orally or pulse doses of methylprednisolone.
o Sustained high doses for several months are usually required to control disease activity.
o Normalization of CK levels precedes improvement in muscle strength by several weeks.
o After several months of treatment, it is usually possible to taper the dose of prednisone, often to an every-other-day regimen.
· Patients whose disease cannot be controlled with corticosteroids can be treated with MTX or azathioprine as steroid-sparing agents.
· IV Igs can be beneficial, particularly in the short term.
· Other approaches to therapy include using immunomodulators such as mycophenolate, tacrolimus, cyclosporine, and rituximab as steroid-sparing agents.
Fibromyalgia
GENERAL PRINCIPLES
· Fibromyalgia is a common cause of musculoskeletal pain. It can be described as a soft tissue amplification syndrome, in which patients experience diffuse musculoskeletal pain.
· Data obtained by functional MRI indicate that pain input is processed differently in the brain in fibromyalgia patients, compared to controls.32
DIAGNOSIS
· History suggestive of fibromyalgia includes diffuse nonarticular pain, sleep disturbance resulting in nonrestorative sleep and fatigue, and accompanying symptoms such as headache, irritable bowel syndrome, paresthesias, depression, and vasomotor symptoms in the hands and feet.
· Physical examination is notable for tenderness to palpation in at least 11 of 18 predetermined tender points. Although the tender points were included in the initial ACR Classification Criteria for Fibromyalgia, opinion is divided as to whether tender points must be present to make the diagnosis.
· Laboratory studies are normal.
TREATMENT
· Treatment has three primary goals: improve sleep, relieve pain, and enhance physical conditioning.
· Non–habit-forming medications that aid in sleep include tricyclic antidepressants (e.g., amitriptyline, 10 to 50 mg qHS), trazodone (25 to 100 mg qHS), and cyclobenzaprine (10 to 20 mg qHS).
· Antidepressant medications (such as venlafaxine, duloxetine, and milnacipran) may also be beneficial. Duloxetine and milnacipran have been shown to be effective in reducing pain in fibromyalgia, regardless of whether depression is present.
· Gabapentin and pregabalin also reduce pain in fibromyalgia. Pregabalin is FDA approved for the treatment of fibromyalgia.
· NSAIDs and other analgesics may bring some relief of pain, but opiates typically require escalating doses to control symptoms and are problematic in the chronic treatment of fibromyalgia.
· An aerobic exercise program is essential and can be supplemented by stretching exercises.
· Cognitive-behavioral therapy programs are also effective.
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