Chapter 53
Chronic Joint Pain (Case 45)
Robin Dibner MD, Joel Mathew MD, and Jessica L. Israel MD
Case: A 32-year-old generally healthy woman complains to her primary-care physician of pain and swelling in her hands. She has noticed for 3 months that her fingers feel stiff in the morning, and she has to place them under warm water to loosen them up. She has difficulty with small buttons when dressing, but by the time she gets to work she feels better and can work on the computer. She has tried over-the-counter ibuprofen with some benefit but feels it is causing dyspepsia. She has not had fevers, rashes, travel, tick bites, or any other new symptoms. She is quite worried, because she has an aunt with arthritis who has “twisted fingers” and a lot of pain. “I think I am too young to have arthritis, right?” she asks.
Differential Diagnosis
Osteoarthritis | Systemic lupus erythematosus (SLE) | Fibromyalgia |
RA | Systemic sclerosis | Seronegative spondyloarthropathies |
Speaking Intelligently
In taking a history from a patient whose arthritis is subacute or chronic, it is important to determine whether the symptoms have been present for longer than 6 weeks. For briefer durations of disease, self-limited entities such as viral arthritides, viral illnesses (e.g., from hepatitis B), and other serum sickness-like reactions from immune complex deposition must also be considered. Infective endocarditis, with an indolent organism such as a viridans streptococcus, is an example of the latter.
PATIENT CARE
Clinical Thinking
• It is important to consider the pattern of joint involvement in a patient who appears to have developed a chronic process—symmetrical or asymmetric? Large or small joints? Upper or lower extremity? The spine?
History
• Women are also affected by RA more often than men.
• Osteoarthritis frequency increases with age.
• The chief complaint defines the specific joints and the pattern of involvement.
• Response to prior treatments is also revealing.
• A functional history can help guide treatment goals.
Physical Examination
• Involved joints should be examined for swelling, tenderness, range of motion, and deformity.
• Inflamed joints often have palpable synovial thickening, which feels doughy.
• The most characteristic joint involvement in RA is involvement of the metacarpophalangeal joints.
• Effusions are more common in inflamed joints but can be present in noninflamed joints.
Tests for Consideration
| Clinical Entities | Medical Knowledge |
Osteoarthritis | |
Pφ | Osteoarthritis occurs as the structural integrity and the chemical composition of joint cartilage wear down and change over time. As this process occurs, there is less protection from friction created as bones rub against other bony structures in the joint. Age, obesity, and chronic repetitive motion on particular joints are all considered risk factors. |
TP | Osteoarthritis typically affects the large weight-bearing joints, distal and proximal interphalangeal joints, and the first carpometacarpal joint of the hand. Patients usually complain of pain with activity that is relieved with rest. Pain at rest, or pain specifically worsening at night, is related to more serious advanced disease. Some patients also present with morning stiffness, but this stiffness generally lasts <30 minutes. Joint swelling is not usually a major feature, but some patients can develop bony outgrowths on the distal (Heberden nodes) and proximal (Bouchard nodes) interphalangeal joints. These can be painful and limit motion. In osteoarthritis of the knee, the examiner may feel crepitus when passively flexing the joint. |
Dx | Osteoarthritis is a clinical diagnosis. The physical findings are surprisingly minimal, especially in early disease. Osteoarthritis of the knees can be reliably diagnosed if the patient is over 50 years of age, has stiffness lasting <30 minutes, crepitus, bony tenderness or enlargement of the joint, and no palpable warmth (American College of Rheumatology clinical criteria). Radiographs of the affected joints may show joint space narrowing, but the findings do not correlate well with disease symptoms. |
Nonpharmacologic treatments include weight loss and changes in activity if repetitive actions are an issue. Physical therapy benefits hip and knee osteoarthritis. Assistive devices (such as jar openers and special kitchen utensils) may also be helpful. Pharmacologically, acetaminophen and NSAIDs are frequently used as a first line, with tramadol and opioids as a second-line therapy. More intensive treatments include corticosteroids and hyaluronan joint injections. Joint replacement therapy is considered when medical therapy is no longer helpful or when the arthritis-related debility has a serious and limiting impact on the patient’s quality of life. See Cecil Essentials 88. | |
Rheumatoid Arthritis | |
Pφ | RA is a complex disease, the cause of which is not completely understood, although much is known about the pathologic process in the joints. The pathology occurs most likely in response to an antigenic trigger. Synovial membranes become thickened and inflamed in the process, and multiple inflammatory mediators are involved. Involved cell types include B lymphocytes, macrophages, and T lymphocytes in the joint space. Cytokines, such as TNF-α and interleukins, also play a major role. Some patients have a clear genetic risk for the disease. |
TP | The disease course and symptoms at presentation can be highly variable. Most patients with persistent synovitis will develop erosive disease in the joints that leads to significant functional limitations. Work disability occurs in a variety of patients within 5 years of diagnosis. The peak age of onset is in the mid-50s, and women are affected more than men. RA usually involves the small joints of the hands and feet symmetrically (wrists, metacarpophalangeal, and proximal interphalangeal joints). Knees are also commonly involved. The joints become painful, swollen, and tender. Sometimes affected joints are warm on examination. Morning stiffness lasting more than 1 hour is also a characteristic feature of active disease. Systemic symptoms can also occur, such as malaise and fatigue. Subcutaneous nodules on extensor surfaces can be palpated in some patients. Extra-articular manifestations of RA include scleritis and episcleritis, pleuritis, pericarditis, secondary Sjögren syndrome, and vasculitis of small and medium vessels. Patients with RA may also have cervical instability at the atlantoaxial articulation, which can be diagnosed with extension and flexion radiographs of the neck. |
A new diagnosis of RA is made based on the history of symptoms for longer than 6 weeks, characteristic patterns of joint swelling and tenderness, and supporting serologic abnormalities including RF positivity and/or anti-CCP positivity. Elevation of the acute-phase reactants ESR or CRP is supportive evidence but neither sensitive nor specific. The American College of Rheumatology and the European Union League Against Rheumatism developed new ACR-EULAR classification criteria for RA in 2010, in part to aid in earlier diagnosis and treatment. Radiographic bone erosion is no longer mentioned in the new criteria, as it is often not evident in early disease. Arthrocentesis is not needed for diagnosis but can be useful to rule out other etiologies of arthritis. | |
Tx | Early and aggressive treatment is essential to slow the progression of the illness and prevent long-term complications. Damage to joints is irreversible, even in the face of disease-modifying agents. Early symptoms may be treated with NSAIDs and corticosteroids. However, early initiation of disease-modifying antirheumatic drugs (DMARD therapy) has been shown to reduce long-term disability and is now the standard of care. Examples of DMARD therapy include hydroxychloroquine, sulfasalazine, and methotrexate, alone or in combination, as well as biologic agents. Biologic agents used in RA include TNF-α inhibitors (etanercept, infliximab, and adalimumab). Patients who do not respond to TNF-α inhibitors may be candidates for abatacept (a T-cell co-stimulation inhibitor) or rituximab (an anti-CD20 monoclonal antibody). Other new biologic agents for RA continue to become available. Patients should be evaluated for latent tuberculosis before starting treatment with a biologic agent and carefully monitored for development of infections. Surgical intervention, including synovectomy or joint replacement, is helpful in patients with advanced or severely destructive joint disease. See Cecil Essentials 79. |
Systemic Lupus Erythematosus | |
Pφ | SLE is an autoimmune disease characterized by a complex dysregulation of the immune system and loss of self-tolerance. Polyclonal B-cell activation, abnormal apoptosis, clearing of cellular debris and immune complexes, and unbalanced production of numerous cytokines are a few of the recognized pathologic mechanisms. This manifests with the presence of autoantibodies, and humoral and cellular inflammation affecting many target organs (kidneys, skin, joints, blood cells, nervous system, and serosal surfaces). |
TP | SLE is much more common in women than in men, and the peak age of onset is between 15 and 45 years. There are multiple clinical features of SLE, and the presentation is variable. Skin involvement may be seen with the classic “butterfly rash” over the cheeks and the nose but sparing the nasolabial fold. Other skin manifestations include discoid lupus, which is a scaly rash usually seen above the neck and often in the ear canals. SLE can also present with a rash that looks similar to psoriasis on the trunk, neck, and extensor surfaces of the body. Alopecia, Raynaud phenomenon, fever, and mucosal ulcers are also associated with SLE. Arthritis and/or arthralgias occur in almost all patients; the joint pain is often migratory and can involve one or many joints in both an asymmetric or symmetrical pattern. About half of patients with SLE will have renal involvement at some point; patients with proliferative lupus nephritis may present with new-onset hypertension or edema. Membranous lupus nephritis presents with nephrotic syndrome. Membranoproliferative glomerulonephritis is also possible, with features of both proliferative and membranous nephropathy. Neurologically, patients with SLE can present with peripheral neuropathies, transverse myelitis, aseptic meningitis, stroke, seizures, cranial neuropathies, or encephalitis. Approximately half of the patients will have pleurisy or pericarditis. Sterile endocarditis (Libman-Sacks), myocarditis, pneumonitis, pulmonary hemorrhage, and interstitial lung disease can also be seen. From a hematologic perspective, patients commonly have various cytopenias, including leukopenia, thrombocytopenia, and hemolytic anemia. Finally, ~40% of patients with SLE have antiphospholipid antibody syndrome, which presents with venous and arterial thrombi and possibly recurrent fetal loss. |
Dx | Lupus is diagnosed based on clinical features and laboratory findings. The American College of Rheumatology uses specific classification criteria for SLE in which at least four criteria need to be present for diagnosis, which can occur at different points in time. The criteria include malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorder, neurologic disorder, hematologic disorder, immunologic disorder (including anti–double-stranded DNA, anti-Smith, or antiphospholipid antibodies), and ANAs. These criteria may be difficult to apply to patients with mild disease. When SLE is suspected, patients should also have, as part of their workup, a CBC, ESR or CRP, and urinalysis. If a patient has a high pretest probability for a diagnosis of SLE and has a positive ANA, he or she should be sent for confirmatory testing, which includes C3, C4, CH50, and anti-dsDNA, anti-Smith, antiribonucleoprotein, anti-Ro/SSA, anti-La/SSB, anticardiolipin antibodies, and the lupus anticoagulant. |
NSAIDs are commonly used to manage the pain in patients with arthralgias and serositis. Hydroxychloroquine is helpful for the skin and joint manifestations, and it can help prevent disease flares. Corticosteroids are a mainstay of treatment for acute SLE flares. Lower doses are used for mild skin or joint involvement. Moderate doses are useful for more aggressive skin and joint disease, serositis, and mild hematologic abnormalities. High doses of corticosteroids are used for nephritis, vasculitis, cerebritis, and serious hematologic abnormalities. Immunosuppressive agents such as cyclophosphamide, mycophenolate mofetil, and azathioprine are steroid-sparing and can improve outcomes for SLE patients with renal disease. The latest therapy for active SLE is belimunab, a monoclonal antibody that inhibits B cell survival by promoting apoptosis and reducing differentiation into antibody-producing plasma cells. It has not, to date, been shown to be effective in renal or CNS lupus. See Cecil Essentials 81. | |
Pφ | Seronegative spondyloarthropathies include ankylosing spondylitis, reactive arthritis (formerly known as Reiter syndrome), enteropathic arthritis, and psoriatic arthritis. Cytokines mediate inflammation in the synovium, entheses, and bone. TNF-α appears to be a major inflammatory mediator in these diseases. There also appears to be a genetic risk and an association with human leukocyte antigen (HLA)-B27 positivity. Infection may also trigger the disease, particularly in patients with reactive arthritis; gonococcal or nongonococcal genitourinary tract infections (with Chlamydia) or infectious diarrhea (with Shigella, Salmonella, Yersinia, or Campylobacter) is associated with reactive arthritis. Patients with HIV may have a higher risk of reactive and psoriatic arthritis. |
TP | The main feature in patients with spondyloarthropathy is enthesitis, inflammation at the junction of tendons and bones, leading to reactive new bone and spur formation. This manifests in the spine as sacroiliitis and spondylitis. The disease usually presents in young patients (<40 years of age). Patients complain of low back and gluteal pain that is worse in the morning and improves with movement or exercise. Over time, spinal joints fuse and the patient may appear to have a forward-flexed position of the spine causing a stooped posture. Commonly, peripheral joints are also affected. These tend to be large joints and are asymmetrically involved, with the exception of psoriatic arthritis, which also involves the smaller joints of the hands and toes. Extra-articular manifestations of the illness may also be present and include inflammatory disease of the skin (erythema nodosum and pyoderma gangrenosum), eyes (conjunctivitis, uveitis, and keratitis), lungs (apical pulmonary fibrosis), vascular system (aortitis), gastrointestinal (GI) tract (inflammatory bowel disease), and genitourinary tract. Ankylosing spondylitis occurs more commonly in men usually in the teenage years and the 20s. Concurrent arthritis of the hips is very common with this condition. Reactive arthritis presents within a few weeks after an episode of bacterial gastroenteritis, urethritis, or cervicitis. The classic triad at presentation of this illness is arthritis, conjunctivitis, and urethritis. The onset of symptoms is acute and is usually an asymmetric arthritis of the lower extremities with or without back pain. Heel pain and swelling from Achilles tendinitis is also common. |
| Enteropathic arthritis accompanies Crohn disease and ulcerative colitis. The arthritis may even develop before the GI component of the disease. The presentation may be an asymmetric large-joint arthritis, usually of the lower extremities, or the spine may be predominantly involved resembling ankylosing spondylitis. The peripheral arthritis activity usually follows the course of the bowel disease, but spine involvement may progress despite remission of the GI symptoms. Extra-articular manifestations are common, especially in the eyes and skin, particularly erythema nodosum. Psoriatic arthritis occurs in 20%–40% of patients with psoriasis, with extensive skin involvement being a marker for risk. The psoriasis predates the development of arthritis by many years in most patients, but it is possible to see the arthritic changes before skin involvement. The typical presentation is a symmetrical polyarthritis that can look very similar to RA. In psoriatic arthritis, however, the distal interphalangeal joints are often involved. Patients often have characteristic pitting and onycholysis in the fingernails. RF is negative in these conditions. |
Dx | Spinal changes can be seen in radiographic studies. Vertebral bodies appear squared, and ossified ligaments lead to the appearance of a “bamboo spine.” MRI of the spine is the best test to detect early spinal inflammation. Peripheral joints may show erosions and destruction, especially in psoriatic arthritis, after chronic involvement. |
Tx | TNF-α inhibitors are the first-line therapy for ankylosing spondylitis, as they can be helpful in both the spinal disease and the peripheral joint and extra-articular components. Traditional immunosuppressants (such as methotrexate and sulfasalazine) help with peripheral and extra-articular disease but not the spinal arthritis. NSAIDs and exercise are also indicated for symptomatic relief and functional improvement. Enteropathic arthritis therapy is now often linked to the treatment of the underlying bowel disease, as the immunosuppressive agents are the same. Corticosteroids, sulfasalazine, azathioprine, and methotrexate may be used for the bowel disease and peripheral arthritis, but treatment of severe bowel disease and spinal involvement often necessitates use of biologic agents such as the TNF-α inhibitors. Psoriatic arthritis treatment is similar to the immunosuppressive treatments used for RA, including methotrexate, sulfasalazine, and TNF-α inhibitors. Corticosteroids are generally not used in this setting, because tapering has been associated with significant flares in skin disease. NSAIDs may help symptomatically but do not alter the disease course or prevent disease progression. See Cecil Essentials 80. |
Fibromyalgia | |
Pφ | The cause of fibromyalgia is not understood but is possibly related to dysregulation of neurotransmitters or central pain sensitization in the central nervous system. Fibromyalgia is associated with low socioeconomic status, poor functional status, and disability. Often there is a preceding history of trauma or an accident before the onset of symptoms. Chronically disturbed, nonrestorative sleep and physical deconditioning may be predisposing factors. “Secondary fibromyalgia” is used to describe symptoms in patients with another defined autoimmune disease who also experience characteristic fibromyalgia symptoms. |
TP | Fibromyalgia presents as chronic widespread musculoskeletal pain for at least 3 months without another diagnosis and symptoms of fatigue, waking unrefreshed, and sometimes cognitive symptoms and a variety of somatic symptoms (e.g., headache, irritable bowel, numbness, and tingling). It is most commonly seen in women, particularly between the ages of 20 and 50 years, although it does also occur in men. The patient’s physical examination is usually normal, except for tenderness to pressure. Previously tenderness at defined “tender points” was used to diagnose the condition, but more recently the combination of chronic pain and other severe subjective symptoms in the absence of another diagnosis is adequate to fulfill criteria for diagnosis. |
Fibromyalgia is a diagnosis of exclusion, and it is important to rule out other disorders, such as hypothyroidism, polymyalgia rheumatica, inflammatory muscle disease, depression, sleep apnea, and restless-leg syndrome. Laboratory studies (such as TSH, ESR, CBC, and CPK) can be helpful to rule out these other possibilities. A sleep study may also be warranted. | |
Tx | Treatment of fibromyalgia involves both pharmacologic and nonpharmacologic interventions. Nonpharmacologic therapy includes regular aerobic exercise as tolerated. Cognitive behavioral therapy has been shown to be effective. Pharmacologically, low-dose tricyclic antidepressants, pregabalin, and duloxetine are the mainstays of treatment. See Cecil Essentials 89. |
Systemic Sclerosis | |
Pφ | Systemic sclerosis is a disease of endothelial cell dysfunction, abnormal fibroblast activity, and autoantibody production. Patients present with symptoms related to microangiopathy and fibrosis in the skin and visceral organs. The disease most commonly affects women aged 30–40 years at onset. African-American patients, especially women, tend to have a more aggressive disease pattern. |
TP | Systemic sclerosis is classified into three forms: limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), and systemic sclerosis sine scleroderma. In lcSSc the skin involvement, which starts distally, usually does not progress proximal to the elbows or knees; however, in CREST syndrome, which is a large subcategory of lcSSc, there is proximal involvement of the upper chest and face. CREST syndrome is an acronym for its manifestations: calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias. Pulmonary hypertension can be a serious complication of lcSSc. In dcSSc there is also diffuse skin thickening in areas proximal to the elbows and knees. In addition, dcSSc is associated with interstitial lung disease and renal disease. In systemic sclerosis sine scleroderma, patients present with characteristic visceral organ involvement without skin pathology. Patients with systemic sclerosis present with typical sclerodermatous skin changes (tightness, thickening, and nonpitting induration extending proximal to the metacarpophalangeal joints). Skin can also thicken around the mouth, causing a smaller oral aperture. Other common presenting symptoms include Raynaud phenomenon (which develops in >95% of patients), myalgias, arthralgias, and myopathy. GI involvement can occur anywhere along the GI tract but is most common in the esophagus; patients usually complain of dysphagia or gastroesophageal reflux symptoms from a dysfunctional lower esophageal sphincter. Related esophageal problems include esophagitis, strictures, and Barrett esophagus. In the small bowel it is not uncommon to see pseudo-obstructions and bacterial overgrowth syndromes; patients may complain of bloating, abdominal pain, and steatorrhea as a result. Lung disease is the main cause of morbidity and mortality in patients with systemic sclerosis. The main pulmonary complications are interstitial lung disease and pulmonary artery hypertension. Patients with interstitial lung disease have dyspnea, cough, and decreased exercise tolerance. Patients with pulmonary artery hypertension present with a decreased exercise tolerance, dyspnea, fatigue, or syncope. About half of the patients with systemic sclerosis will have some cardiac involvement including cardiomyopathy, systolic or diastolic dysfunction, pericarditis, and arrhythmias. It’s important to note that cardiac disease in these patients, while present, can also be clinically silent. Scleroderma renal crisis is seen in dcSSC and is a medical emergency; patients present with hypertensive urgency or emergency, kidney failure, and microangiopathic hemolytic anemia. |
Dx | The diagnosis of systemic sclerosis is made in patients who have characteristic skin changes or two of the following features: sclerodactyly, digital pitting, or basilar fibrotic infiltrates on chest radiograph. Ninety-five percent of patients with this illness have antinuclear antibodies in the blood; many exhibit a nucleolar staining pattern. Anticentromere antibody is associated with CREST and a low risk of interstitial lung disease. Anti–topoisomerase I (also known as anti-scl-70) is associated with dcSSc and a higher risk of interstitial lung disease. |
Tx | There is no overall treatment for systemic sclerosis, so therapy is aimed at specific manifestations. Vasodilators (such as calcium channel blockers, nitrates, α1-antagonists, and sildenafil) can be helpful in managing Raynaud phenomenon. Some patients need more significant interventions such as sympathetic nerve blockade or endothelin antagonists. |
