Inflammatory leg pain – Inflammatory diseases
A foreign stimulus causes the body to mount an inflammatory reaction to maintain its integrity. When an organism or foreign protein penetrates the body surface, a series of host responses occurs. The inflammatory exudate containing immunoglobulin, complement components and other plasma proteins quickly appears. Cellular and humoral immunological pathways and the components of inflammation and repair produce widely disparate manifestations developing over hours in crystalline (gout, pseudogout) disease and septic arthritis to years in the case of rheumatoid arthritis (RA). Its clinical manifesta-tions may involve single to many joints to multisystem diseases such as systemic lupus erythematosus (SLE) or vasculitis.
Inflammation varies in intensity and extent and in the particular im-munological pathways evoked, but certain features are common to all forms whether it is an acute allergic response or a chronic granulomatous process. Effectors of inflammation exist in precursor forms and are activated. A number of proteins modulate the inflammatory effects and a number of pathways with feedback loops which can amplify the inflammatory process.
Many systemic rheumatic diseases such as RA and SLE are considered to be of autoimmune origin and multifactorial. It is believed that initiating events trigger a pathological process in a genetically susceptible individual in which immune response persists and leads to tissue inflammation and destruction. However, only a fraction of susceptible individuals develop disease. Many rheumatic diseases have strong genetic patterns and others demonstrate polytonic inheritance. For example, ankylosing spondylitis is associated with HLA-B27, RA with HLA-DR4 and DR1, and SLE with null alleles of C4A.
Signs and symptoms
The classic pathological features of inflammation are: pain (dolor), swelling (tumor), heat (calor), redness (rubor). Depending on the tissue and the site involved, some features may be more obvious than others. A joint effusion implies synovitis and points to a structure inside or next to the joint capsule as the cause of the problem. In primary care settings, a small- to moderate-sized effusion in the knee only is likely to be due to microtrauma to the meniscus or ligaments, viral illness, or, less frequently, to early RA or to the spondyloarthropathies.
Some distinctive patterns of synovitis are useful in the differential diagnosis of arthritis. Septic arthritis and crystalline disease of the joints typically affect one joint but can also affect two or more joints simultaneously. The pain comes on abruptly and reaches its maximum over hours to a day. Pain occurs at rest unrelated to joint use and may also be associated with systemic symptoms and low-grade fever. Acute podagra (gout of the first metatarsalphalangeal (MTP) joint) and pseudogout of the knee are classical presentations, but crystalline disease and septic arthritis look identical and infection must always be excluded by aspirating the joint for synovial fluid cultures and examination for crystals and Gram stain.
Synovitis from systemic rheumatic diseases or spondyloarthropathy produces joint stiffness early on. When severe inflammation occurs or is uncontrolled, structural damage occurs and mechanical pain symptoms dominate. Early synovitis causes variable joint symptoms. Patients complain typically of ‘good’ and ‘bad’ days. Stiffness is worst after prolonged activity (‘gelling’), which improves after using the involved joint. In some patients this can be used to assess the severity of the synovitis. As the synovitis improves the length of gelling also shortens. In other patients with synovitis, gelling may not be prominent or can ‘last all day’. A reliable way to ascertain gelling is to ask when the subject awakens and when they are feeling the way they will be for the rest of the day. With advanced disease and joint destruction, pain is constantly produced by anything that loads the joint and relieved by unloading the joint.
Inflammatory diseases Infectious arthritis
Etiology and pathogenesis
Joint inflammation can result from direct invasion of the joint by bacterial, microbacterial, viral, fungal, and even parasitic infections or as a sterile inflammation in which the organism cannot be isolated or cultured, a group of conditions conceptualized as a hypersensitive or reactive arthritis (acute rheumatic fever, Reiter’s disease). Septic arthritis, particularly with acute bacterial pathogens, is a serious cause of morbidity and mortality, joint damage, and functional disability.
Bacteria may seed the joint as a result of direct trauma, surgery, or arthrocentesis, by extension from an adjacent focus of infection, or through the blood from a remote source. Once inside the joint cavity, bacteria can rapidly multiply and cause an inflammatory reaction that is highly destructive to the tissues of the joint space. The most common bacterial pathogens are Staphylococcus aureus, Gram-negative bacilli, and mixed aerobic/anaerobic infections. Indolent infections with mycobacteria and fungi cause < 5% of joint infections. Disseminated gonococcal infections with joint involvement or symptoms are common in sexually active patients.
A variety of clinical settings is associated with an increased risk of joint sepsis. These include previous joint damage or inflammation, prior joint surgery, immunocompromised host and bacteremia (pyelonephritis, bacterial endocarditis).
Clinical manifestations and diagnosis
Signs of infection such as leukocytosis, elevated erythrocyte sedimentation rate and fever may not be present, and the only way to make the diagnosis is to culture the joint fluid. Therefore, a joint aspiration is always required when-ever there is a possibility of infectious arthritis. The fluid should be cultured in the appropriate medium and a Gram stain should be done on fresh fluid. The yield of cultures or Gram stains depends on the specific infectious agent. In suspected gonococcal arthritis, the synovial fluid should be plated on Thayer–Martin blood agar and put immediately under CO2 to increase the yield of growth. Gonococcus is recovered in < 50% of suspected individuals. Mycobacteria and fungi can be recovered in well over half of the patients by synovial fluid culture, but the diagnostic yield can be increased considerably by doing a synovial biopsy with culture and histology. Blood cultures should always be obtained because many infections of the joint are metastatic infections from other sources.
Differentiating cellulitis from a septic joint may pose a diagnostic problem. Pain from septic arthritis is equally painful in all ranges of motion. Pain from cellulitis hurts most when the joint motion stretches the cellulitic areas. Swelling and erythema in a septic joint occur over the entire circumference of the joint line, whereas cellulitis is more localized. When in doubt, the joint should be aspirated for culture, avoiding the area of inflamed skin.
In a patient with pre-existing polyarthritis, infection of the joint may be difficult to diagnose because it occurs on the background of multiple joint symptoms. When there is one joint that is painful out of proportion to the others one should suspect infection.
Non-gonococcal arthritis is caused by a variety of infectious agents, chiefly S. aureus, streptococcal species, and Gram-negative bacilli. Non-gonococcal arthritis generally affects a single joint, most commonly a weight-bearing joint, and especially the knee. X-rays of the joint early on show only soft-tissue swelling. It may take weeks before other X-ray signs of periosteal elevation, bone destruction, and joint-space narrowing are seen. Gallium and bone scanning detect changes earlier than plain radiographs. Nuclear magnetic resonance imaging is more sensitive to anatomic changes.
Gonococcal arthritis should be suspected in any person who is sexually active. A common presentation is a woman who presents around the time of her menses with migratory polyarthralgias and severe tenosynovitis, particularly of the wrist. A characteristic skin rash may occur in two-thirds of patients and tends to be a scantily distributed painless maculopapular, pustular, or vesicular eruption, classically a gun-metal gray lesion on an erythematous base. It requires a careful search to find. Cervical, anal, oral, and blood cultures for gonococcus increase the yield, but some cases are never confirmed and are diagnosed only by their prompt response to antibiotics.
Gonococcal arthritis needs to be differentiated from Reiter’s syndrome in men. A typical hemorrhagic skin rash would favor gonococcus. Additional differential points include a preponderance of lower extremity involvement among patients with Reiter’s syndrome. Gonococcal arthritis more commonly affects the upper extremity and presents as a migratory arthritis. Achilles tendinitis, plantar faciitis, and uveitis are almost never seen in gonococcal arthritis but occur in Reiter’s syndrome. Keratoderma blennorrhagia, a hyperkeratotic skin lesion frequently on the soles of the feet, clinches the diagnosis of Reiter’s syndrome. Gonococcal infection of the pharynx or rectum would favor a gonococcal arthritis.
Many viral arthritides have been described, including hepatitis B, parvovirus, rubella, and mumps. In general, viral arthritides result from hyper-sensitivity or immune complex disease. Clinically they look like RA and have tantalized investigators to link viruses and RA. Most of these arthritis syndromes resolve by 4–6 weeks. Rubella and parvovirus may cause chronic synovitis in a small percentage of patients.
Bacterial endocarditis may be associated with septic arthritis, which is rare, or with sterile, inflammatory synovitis. The latter manifestation is probably due to hypersensitivity or an immune-mediated process. Polyarthritis and polyarthralgias, monoarthritis, myalgias, hypertrophic osteoarthropathy, disc infection, and low back pain are also syndromes seen in association with endocarditis.
Tuberculous arthritis has declined in incidence but still occurs in immuno-compromised patients such as AIDS patients, alcoholics and the homeless. Joint and bone infections occur from hematogenous spread and contiguous infection from infected bone. Classically, tuberculous arthritis presents as a chronic insidious monoarthritis with few of the typical findings of inflammation (a ‘cold abscess’). The most commonly involved sites are the vertebral column (Pott’s disease) and weight-bearing joints. Chronic tenosynovitis may also be caused by mycobacteria species.
Lyme disease has arthritis as a manifestation and is caused by a spirochete, Borrielia burgdorferi. It presents with a characteristic skin lesion, Erythema chronicum migrans (EM), a red maculopapular rash that expands to an annular (‘target’) lesion 3 days to 3 weeks after a bite from an Ixodes dammini tick carrying the spirochete. EM is often accompanied by chills, fever, malaise, fatigue, and headache or stiff neck. Weeks to months later, neurological, cardiac and joint complications may occur. Joint symptoms occur in about 50% of patients and include migratory polyarthritis without morning stiffness and tendinitis, and they may recur. Chronic monoarticular involvement of a large joint, usually a knee, is uncommon and over time usu-ally resolves.
Neurological abnormalities may occur within a few weeks after EM, last for months, and usually resolve. These include aseptic meningitis or meningoen-cephalitis, chorea, cerebellar ataxia, cranial neuritis including bilateral Bell’s palsy, motor and sensory neuropathy, radicular neuritis, and mononeuritis multiplex. Cardiac abnormalities also arise within a few weeks after EM and include atrioventricular heart block and myopericarditis.
Identification of the organism is the key to successful treatment with antibiotics. Infections in closed spaces need to be drained. Closed-needle joint aspiration will suffice, except in hips and shoulders, where open drainage is usually required. All suspected or proven joint infections require consultation and hospitalization.
Early on, the joint should be immobilized with splints to help make the patient more comfortable, but exercises should be started as soon as pain subsides to prevent muscle atrophy and contracture. If the effusion does not resolve, joint aspiration should be repeated to reduce the volume of fluid and enhance comfort and full joint extension.
Depending on how quickly the fluid reaccumulates, three arthrocenteses a day to one every 3 days may need to be done. Evidence clearly shows that delay in drainage, particularly delay beyond 72 h from the onset of symptoms, is the largest determinant of whether the patient becomes septicemic and whether there are complications such as osteomyelitis and significant cartilage loss. A joint infection by S. aureus can destroy cartilage in 48 h. At the other end of the spectrum, most cases of gonococcal arthritis do not result in joint damage.
A falling joint-fluid cell count and minimal reaccumulation of fluid indicate a good clinical response. Repeated closed arthrocentesis with a needle can produce good results 80% of the time, but one should go to open drainage after 3 days if the patient is not substantially improved and if the volume of arthrocentesis fluid and the cell count in the fluid are not dropping rapidly.
Open drainage should be done early in certain situations. Infections in the hand are dangerous because compartment syndromes may develop rapidly. The shoulder has multiple anatomical compartments and may not be drained completely through a needle. Hips and shoulders always require surgical drainage.
Another question that commonly arises in the treatment of septic arthritis is the duration of antibiotic treatment. As a rule, gonococcal joint infections can be treated for 2 weeks, and all others are treated for a minimum of 4–6 weeks. Intra-articular antibiotics are not used because they create chemical inflammation and because the drug levels obtained by intravenous antibiotics are adequate. Ancillary treatments are useful. Non-steroidal anti-inflammatory drugs (NSAIDs) and joint rest help relieve pain. Continuous passive motion for a septic knee is used to maintain the range of motion.
Patients with gonococcal arthritis should be considered for admission to hospital if there is a frankly purulent effusion, diabetes, poor comprehension and social support or no transportation or home telephone. Effective antibiotic regimens for disseminated gonococcal infection include: ceftriaxone 1 g i.v. daily for 7–10 days or for 2–3 days, followup by cefixime 400 mg oral bid or ciprofloxacin 500 mg oral bid for a total of 7–10 days. Appropriate antibiotics usually reverse the symptoms within 24–48 h. Repeated joint drainage of the effusion is seldom required.
Treatment of tuberculous arthritis requires long-term administration of multiple antibiotics and should always be done with consultation. Fungal arthritis is also rare and has a clinical presentation similar to mycobacterial arthritis. Fungal infections of bone and joint include coccidioidomycosis, sporotrichosis, blastomycosis, and candidiasis. Consultation is suggested.
For the treatment of Lyme disease, oral antibiotics are effective except for neurological and cardiac manifestations. In early localized Lyme disease, doxycycline 100 mg bid and amoxicillin 500 mg qid for 14 days are effective. In patients with allergies to the above medications, cefuroxime 500 mg bid and erythromycin 250 mg qid seem to be good alternatives. Doxycycline should not be given to children or pregnant women. In children under age 12, amoxi-cillin is effective in divided dosages of 50 mg/kg per day. In cases of penicillin allergy, erythromycin (30 mg/kg per day) can be given. For disseminated infection and arthritis, oral regimens should be given for a month. For neurological and cardiac disease intravenous therapy with ceftriaxone 2 g/day for a month is recommended.