Seronegative and Seropositive Rheumatologic Disorders Affecting the Lower Extremity

STEPHEN J. DIMARTINO

Rheumatic diseases and other inflammatory disorders of the lower extremity are seen less commonly than mechanical conditions and local injuries. But because all inflammatory disorders may present in a similar fashion and because some have the potential to cause permanent damage without appropriate therapy, one must always be on the alert for their presence. Inflammatory disorders can be grouped into several categories: autoimmune, crystalline, and infectious (Table 2-1). In general, these conditions are systemic and, therefore, may involve the upper extremities and spine as well as organ systems outside of the musculoskeletal. Indeed, the pattern of joint involvement combined with associated symptoms (e.g., rash, oral ulcers, inflammation of the eye, interstitial lung disease) may be the most important clues to identify a systemic illness. Some systemic illnesses tend to favor the lower extremities such as gout, spondyloarthropathy, Lyme disease, and sarcoidosis (Lofgren syndrome), but they all will often involve other body regions. Therefore, it is important to always perform a careful history and physical examination when inflammatory disease is suspected.

Special Considerations in the Approach to Potential Inflammatory Disease

Urgent and Emergent Conditions

Failure to recognize certain conditions may lead to irreversible morbidity or mortality. These include septic monoarthritis, systemic sepsis, osteomyelitis, compartment syndrome, cellulitis, deep venous thrombosis (DVT), ischemia or infarction due to embolus, thrombosis or vasospasm, fracture, spinal cord compression, mononeuritis multiplex, and vasculitis (Table 2-2). The following features of the history and exam, though frequently nonspecific, can be helpful to direct one toward more urgent testing.¹,²

Inability to Bear Weight

The inability to bear weight on a joint raises suspicion of fracture, a septic joint/prosthesis, or gout. Usually, a history of trauma will prompt workup for fracture; however, in patients with osteoporosis, fractures may occur with minimal trauma. Risk factors for osteoporosis include being postmenopausal, prior or current use of corticosteroids, smoking, low body mass, a personal history of fracture, a family history of hip fracture, inflammatory disease such as rheumatoid arthritis, excessive alcohol intake, and low vitamin D.3 Furthermore, spontaneous fractures may occur in patients with an underlying tumor or, in rare instances, in patients taking bisphosphonates.⁴

Table 2-1. List of Inflammatory Disorders of the Lower Extremity

Autoimmune
Rheumatoid arthritis
Spondyloarthropathy
	Ankylosing spondylitis
	Psoriatic arthritis
	Reactive arthritis
	Enteropathic arthritis (associated with inflammatory bowel disease)
	SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis)
Sarcoidosis
Systemic lupus erythematosus
Inflammatory myopathy: especially antisynthetase syndrome
Crystalline
Gout (monosodium urate)
Pseudogout (calcium pyrophosphate)
Basic calcium phosphate deposition
Infectious
Lyme disease
Parvovirus
Gonococcus
Poststreptococcal reactive arthritis and rheumatic fever
Alfa viruses such as chikungunya
Tuberculosis (direct seeding of joints or reactive)
Fungal

Table 2-2. Urgent/Emergent Conditions

Septic monoarthritis

Systemic sepsis

Osteomyelitis

Compartment syndrome

Cellulitis

Deep venous thrombosis

Ischemia/infarction due to thrombus

Raynaud phenomenon associated with gangrene

Fracture

Spinal cord compression

Mononeuritis multiplex

Vasculitis

Erythema

Erythema of a joint is rarely seen in patients with systemic inflammatory disorders such as rheumatoid arthritis or spondyloarthropathy. The presence of erythema raises suspicion for a septic joint, gout, or cellulitis. When a cellulitis lies over a joint, it can be a challenge to distinguish it from gout or septic arthritis because it may also limit range of motion of the joint owing to pain caused by stretching of the skin and subcutaneous tissues. An obvious portal of entry or an off-center distribution of erythema (relative to the joint space) can be helpful clues to cellulitis, if present. Although gout is often thought of as a condition isolated to joints, tenosynovium and subcutaneous tissue are commonly involved, and when this occurs it can also cause an off-center distribution of erythema on the joint. Point-of-care musculoskeletal ultrasound (MSKUS) can be valuable in these situations, as it will show edema in the subcutaneous fat in the case of cellulitis or can show joint/tendon involvement in the cases of gout or septic arthritis.

Constitutional Symptoms

Although many systemic autoimmune conditions and even crystalline arthropathy can present with constitutional symptoms, the presence of fever, malaise, weight loss, and/or an elevated leukocyte count should prompt the clinician to rule out infection. Blood cultures, synovial fluid cultures, and culture of other distant symptomatic sites are necessary. Patients with known underlying conditions that can cause fever such as systemic lupus erythematosus (SLE) or systemic vasculitis often take immunosuppressive drugs, increasing the risk of infection. Therefore, when these patients present with a fever, it is difficult to discern whether there is a flare of disease, an infection, or both. Also, it is important to note that corticosteroids will often cause an elevation in the WBC count, confounding a situation where infection needs to be ruled out. Moreover, patients who are on corticosteroids, especially doses greater than 30 mg of prednisone daily (or the equivalent), may not mount a fever even when septic, or they may have reduced symptoms in the setting of an infection. In a patient taking high doses of corticosteroids, any infection has likely been present longer than one might suspect based on their symptoms; therefore, one must have a low threshold to initiate antibiotic therapy as soon as is possible.

Neurologic Symptoms

Weakness, numbness, paresthesia, and a burning quality of pain can all be clues to neurologic involvement such as radiculopathy, myelopathy, compartment syndrome, or mononeuritis multiplex/vasculitis. It is important to keep in mind that pain in a joint will often result in weakness, making assessment of strength challenging. Furthermore, inflammation in a region in which a peripheral nerve passes through (such as the tarsal tunnel or volar wrist) can lead to compression of the nerve and resultant paresthesia or numbness.

Diffuse Edema

Diffuse edema, especially when unilateral, may raise suspicion for the presence of a DVT. The typical presentation of a DVT is that of pain, swelling, and erythema on the lower extremity; however, all of these symptoms need not be present, and there are many other conditions such as venous insufficiency, popliteal cysts, cellulitis, and muscle injury that may present in a similar fashion. Furthermore, arthritis or periarthritis of the ankle, which may be seen in any type of systemic inflammatory arthritis, may present this way. Risk factors for DVT include states that promote hypercoagulability such as recent surgery or injury, pregnancy, malignancy, genetic hypercoagulable states such as Factor V Leiden, and autoimmune conditions such as the antiphospholipid antibody symptoms and granulomatous angiitis.⁵ A personal or family history of DVT is also a risk factor. Diagnosis can be made with ultrasound of the lower extremity; the location of the clot often does not correlate with the location of symptoms. Treatment of DVT with anticoagulation is critical to reduce the risk of pulmonary embolus.

Articular versus Periarticular Disorders

Patients who present with a complaint of joint pain often find it difficult to distinguish between a true articular problem and a periarticular disorder. In general, an articular disorder will be associated with pain throughout the range of motion of the joint involved, whereas a periarticular disorder (e.g., tendonitis, bursitis) will be associated with pain through only a segment of the full range of motion. Well-localized tenderness over a tendon or bursa further supports the conclusion of a periarticular disorder. It is not only possible, but rather common for both processes to occur simultaneously during an inflammatory illness. Therefore, the presence of periarticular pain does exclude the existence of a systemic inflammatory disorder. For example, rheumatoid arthritis frequently affects tendons in addition to joints⁶ and may in fact be common in early presentation of the disease. In gout, uric acid crystals
may not only deposit in joints and tendons but also disperse to surrounding soft tissue. In spondyloarthropathy, the major target of the autoimmune attack is the enthesis: the attachment of tendons and ligaments to bone.⁷ Therefore, patients will often present with both clear synovitis manifested by tenderness and swelling of a joint with pain throughout the range of motion and also localized tenderness over a nearby tendon such as the Achilles, quadriceps, or patellar tendons.

Monoarticular Arthritis versus Oligo-/Polyarticular Arthritis

Septic arthritis, traumatic arthritis, and crystalline arthritis (i.e., gout, pseudogout) are the main entities to consider when a patient presents with monoarticular joint pain. However, it is important to keep in mind that gout and pseudogout can involve more joints in a significant proportion of patients, and can even present, albeit rarely, as a symmetric polyarthritis of the small joints of the hands and feet, mimicking rheumatoid arthritis. Furthermore, any typically polyarticular process such as rheumatoid arthritis and spondyloarthropathy can present as monoarticular disease, especially early in the disease course and especially with onset in the elderly. After working up a monoarticular arthritis for infection, injury, and crystalline disease, it is important to give consideration to systemic inflammatory disease. The failure to recognize a systemic condition that has manifested atypically as a monoarticular arthritis may result in multiple unnecessary procedures, including surgery. Increasingly, MSKUS has been found to be useful in distinguishing between mono- and oligo-/polyarticular disorders and articular versus periarticular disorders.

Use of Ultrasound in Rheumatology

Over the last 10 to 15 years, MSKUS has become an established technique for evaluation and follow-up of patients with rheumatic diseases. Technologic advances, including faster computers and probes that can see greater detail, allow even today’s low-budget machines to detect tiny fluid collections within joints, resolve small defects in bone and cartilage, and provide color maps of the joint, indicating where inflammation is taking place. The advantages of ultrasound over other imaging modalities include the following: portability due to the small size of the machines, noninvasiveness, lack of radiation (allowing for frequent repeat imaging), relative inexpensiveness, the ability to scan multiple joints in a brief period, and the ability to look at the joint while it is in motion (i.e., dynamic imaging). These features make ultrasound particularly well suited not only for the diagnosis of rheumatic disease but also for monitoring the progress of therapy. Therefore, a rheumatologist with a clinical understanding of the patient’s problem can scan and interpret images at the bedside, rather than sending the patient for a second appointment. Treatment decisions can be made immediately, thereby greatly improving the efficiency of medical care. Finally, ultrasound at the bedside has tremendous educational value for the patient as they struggle to understand their own disease process. With only brief explanations, the patients can see real-time images of the inflammatory process damaging their joint, making a concrete notion of what was previously only abstract. This is of great utility to the practitioner when discussing the reasons for medical therapy, which are often immunosuppressive or chemotherapeutic drugs with numerous toxicities.

Indeed, a large body of literature supports the above assertions. For example, studies examining the utility of ultrasound in the rheumatology clinic have shown that ultrasound is more accurate than clinical examination at detecting joint fluid and inflammation.⁸,⁹ In a study of 100 consecutive patients, Karim et al.¹⁰ have shown that use of ultrasound in a busy outpatient rheumatology clinic changed the management plan that was made prior to the performance of ultrasound 56% of the time and that overall diagnosis was changed 5% of the time. Several studies¹¹,¹²,¹³ have shown that, in rheumatoid arthritis, baseline power Doppler signal is a strong predictor of joint damage 1 year later.

For several types of inflammatory arthritis, studies have examined the role of performing ultrasound in rheumatic disease patients with the following aims: clarifying the differential diagnosis in early, undifferentiated rheumatic disease, defining the number of joints inflamed and/or damaged, monitoring the success of therapy in established disease, guidance of joint aspirations and injections. Indeed, there have been a growing number of rheumatologists using point-of-care ultrasound to enhance patient care in recent years.¹⁴

When and Why to Refer a Patient with Suspected Inflammatory Arthritis

In the past several decades, studies in cohorts of patients with early inflammatory arthritis (not fulfilling the American College of Rheumatology criteria of rheumatoid arthritis at onset) have shown that while many of these patients have a self-limited illness, a significant proportion of these patients go on to develop rheumatoid arthritis (RA).¹⁵,¹⁶ Several observations have led to the conclusion that RA patients should be identified early and treated aggressively. Machold and colleagues¹⁵ have shown in a study of patients with inflammatory joint disease of less than 3 months’ duration that 61.1% of patients went on to develop rheumatoid arthritis, 12.8% had erosions on their first X-rays, and 27.6% had erosions by their first year. This highlights the fact that permanent joint damage can begin very early in the disease process. In addition, many patients with RA are forced to leave work within 5 to 10 years of disease onset, and life spans of RA patients are significantly shortened. The persistent inflammatory burden associated with RA can lead to premature atherosclerosis and death due to cardiac events. Data such as these have led investigators to compare treatment strategies in patients with early inflammatory arthritis.

There is now clear evidence that patients who have early rheumatoid arthritis have significantly better outcomes when they are treated within the first few weeks to months of their illness. For example, Lard and colleagues¹⁷ have shown (utilizing medications that are now considered relatively weak disease-modifying antirheumatic drugs (DMARDs)) that treatment initiated within a few weeks of symptom onset resulted in less radiographic damage (as measured by Sharp score) and less overall disease activity (as measured by the disease activity score).

Furthermore, over the last 15 years, the introduction of biologic medications, especially those that block tumor necrosis factor α (TNF-α), has revolutionized the practice of rheumatology, allowing for greater control of the inflammation of RA than was previously possible. The TNF-α blockers, which include etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol, not only greatly reduce disease activity but also can slow the progression of joint destruction. Because early treatment results in better outcomes and because we now have very effective agents for doing so, early inflammatory arthritis should be treated with a sense of urgency. While RA is the classic inflammatory arthritis, there are many other conditions that are virtually indistinguishable from RA early in their course, some of which can be equally destructive, but may require different or additional therapies. These diseases include (but are certainly not limited to) the following: SLE, psoriatic arthritis (PsA), ankylosing spondylitis, systemic sclerosis, relapsing polychondritis, inflammatory myositis, granulomatous angiitis, adult-onset Still disease, polymyalgia rheumatica, and giant cell arteritis.

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