The Differential Diagnosis of Arthralgia

The Differential Diagnosis of Arthralgia ARNALDO G. CARVALHO, M.D. LUIS FERNANDEZ-HERLIHY, M.D.

arthralgia refers to the symptom of joint pain. "Arthritis" denotes inflammation or other objective pathologic findings in one or more joints. This paper is limited to a discussion of the differential diagnosis of arthralgia, emphasizing the clues furnished by a carefully taken history and the physical examination. The importance of evaluating this symptom is obvious when one considers that about one person out of 18 in the United States has a rheumatic disorder of some form. Arthralgia occurs in a wide variety of conditions, ranging in significance from the simple "flu" to several types of malignant disease. It can be shown that a carefully taken history is of the utmost value in evaluating the significance of articular symptoms. In a patient with arthralgia, several important historical events should be sought for: 1. What was his general health at the onset? 2. Are any constitutional symptoms present? 3. How many joints are involved? 4. Which joints are involved? 5. In what order did they become involved? 6. Were they involved simultaneously or in succession? 7. What was the duration of symptoms a. in each joint? b. of the whole attack? 8. How do the following affect the symptoms? a. weather changes b. heat c. salicylates d. rest e. activity 9. How severe is the pain? Does it require narcotics? Does it wake the patient from a sound sleep?

THE TERM

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CONDITIONS IN WHICH ARTHRALGIA IS USUALLY THE CHIEF COMPLAINT

About 80 per cent of all patients whose cHief complaint is arthralgia will have one of the following conditions: rheumatoid arthritis, degenerative joint disease, gout, bursitis (or other nfibrositic" syndrome localized to the joint), or psychogenic rheumatism. The complete list would include joint trauma, septic arthritis, rheumatic fever, Reiter's syndrome, and intermittent hydrarthrosis. The maindi,stinguishing features of the most common of these conditions are outlined in' Table 1. Rheumatoid Arthritis (Table 1)

Rheumatoid arthritis accounts for 30 to 40 per cent of all cases of "rheumatism" and is the commonest cause of acute arthritis in adults. Usually:, no precipitating factor is found ..The onset maybe .8Jldden or gradual. If the. pro~~~s is monarticular at the onset, it isu~llsual for a long period of time to elapse without ad
Distinguishing Features of Most Common NO. OF PERIPHERAL JOINTS

AGE AT ONSET

SEX

SYMPTOMATIC .

JOINT PREDILECTION

SYMMETRY

Rheumatoid Arthritis

80% between :F'emales,4:1 25-50 yrs. ,I

Usually multipie; almost simultaneously

Small joints with :Striking centripetal ' spread

Rheumatoid Spondylitis

15-40 yrs.

A few in 25% of patients

Degenerative .. Joint Disease

Over 30 yrs.; N a predomi- One or a few earlier in nance obesity or after injury Usually one Any age Either

Sacro-iliac joints Usually present and spine; hips, if peripheral knees, ankles in joints involved 25% Weight-bearing N at characterjoints; PIP and istic Mep joints almost never Any III Absent.

I

Joint Trauma Gout

Males, 9: 1

.'

Over 30 yrs.

Males. 95 %

One in 95 % of early attacks

Psychogenic Rheumatism Rheumatic Fever

30-60 yrs.

Mainly females

Multipleor "all"

90 % under 15 yrs.

Either

Multiple, in succession

Large joints; small joints of feet ,.

Often present

Reiter's Syndrome

20-30 yrs.

Males; rarely in females

M ultiple

Knees; ankles; feet

Variable

Bursitis and Other Fibrositi(f Syndromes

Usually over 20 yrs.

Either

Usually one

Shoulders

Usually absent

Peripheral small joints; especially first MTP Any

Absent Often present

•

ASA. Acetylsalicylic acid (aspirin); DIP, distal interphalangeal joints; PIP, proximal interphalangeal

1 he Differential Diagnosis of Arthralgia 1

absenee. r-rhe spine is not involved, although "soreness" of the spine may be present as part of the general feeling of malaise. Morning stiffness is generalized and persistent and it usually takes longer than a half hour for the patient to "limber up." Constitutional symptoms are often present: fatigue out of proportion to pain, joint involvement or muscle atrophy, anorexia, depression, irritability, weight loss, and low grade fever. Physical examination may reveal that the patient looks ill, a reminder that rheumatoid arthritis is a systemic disease. Moisture of the palms and soles is common, and palmar erythema ("liver palms") is a frequent finding except in the steroid-treated patient. Rheumatoid nodules are an important finding and their presence is almost pathognomonic of rheumatoid arthritis. They vary in size and they occur most frequently over the ulnar surface just distal to the olecranon. They are found also on the tendons of the fingers, the Achilles tendon and over the occipital area. 1-'hey may appear at some time in 20 to :30 per cent of all patients with rheumatoid arthritis. Occasionally these nodules may be mistaken for exostosis since they are often adherent to periosteum. Muscular atrophy is an important physical finding and may be seen quite early in the disease, usually in the distal musculaConditions in Which Arthralgia Is Chief Complaint INFLUENCE OF WEATHER, NATURE OF PAIN

ASA, HEAT, ACTIVITY

Rarely intolerable

Aggravated by weather changes; relieved by ASA, heat; stiffness after rest; improves with motion

Same as rheumatoid arthritis

Same as rheumatoid arthritis

"Aching"; occasionally severe

Same as rheumatoid arthritis in affected joint; worse with motion or weight bearing Same as degenerative joint disease None except during attack; then as in degenerative joint disease "Nothing relieves it"

Variable Excruciating "Aching"; "tightening" Same as rheumatoid arthritis

Dramatic response to salicylates

Same as rheumatoid arthritis

Same as rheumatoid arthritis

Variable

Aggravated by weather changes and inactivity; relieved by heat, ASA

ADDITION AL CLUES

DURATION OF SYMPTOMS

One episode lasts weeks; Metatarsalgia; heel or bilat. shoulder pain; insymptoms may be convolvement of temportinuous for years omandibular joint; ocular comp. (10%); rheumatoid nodules Night pain in back; alterWeeks to years nating sciatica; iritis Obesity; joint crepitus; "bony" swellings

Sporadic to years

Variable

History of inj ury

4-10 days in early attacks

Appearance of litis"; tophi

Variable; may last for years

M ultiple system plaints

1-7 days for each joint;

Abnormal cardiac findings

weeks to months for attack 4-10 weeks for attack

Variable; may recur over years

"cellucom-

Urethritis; conjunctivitis rashes; rarely diarrhea at onset N one particularly

joints; Mep, metacarpophalangeal joints; MTP, metatarsophalangeal joints.

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ture (thenar, hypothenar, interosseous). Slight, generalized lymphadenopathy may be found. Typical changes in the hands and feet are relatively late manifestations. Only 9 per cent of the patients show ulnar drift of the fingers within the first five years of the disease. Progressive hallux valgus may be a relatively early manifestation. In early cases the only radiologic changes may be juxta-articular demineralization and narrowing of the joint spaces, particularly in the small joints, and a roentgenogram of the hands is a very useful diagnostic procedure. Laboratory studies may show anemia, leukocytosis and a high sedimentation rate. Serologic tests for rheumatoid factor will be positive in 75 per cent of all cases of rheumatoid arthritis but may be negative in the first few months of illness. The test is positive in almost all patients with rheumatoid nodules. A positive L.E. test is found in about 15 per cent of patients with chronic, deforming rheumatoid arthritis, but in about 30 per cent of patients who are on steroid treatment. Juvenile rheumatoid arthritis, or Still's disease, is rheumatoid arthritis with onset before puberty. It is similar to the adult form but the cervical spine is frequently affected, and splenomegaly, lymphadenopathy and leukocytosis are found perhaps more frequently than in the adult. The peak of age incidence at the onset is two to three years. The results of serologic tests for rheumatoid factor are frequently negative in juvenile rheumatoid arthritis. CONDITIONS CLOSELY RELATED TO RHEUMATOID ARTHRITIS. 1. Psoriatic Arthropathy. Psoriasis may precede, accompany or follow arthritis. rI'wo clinical types of arthritis are recognized: one indistinguishable from rheumatoid arthritis and the other characterized by psoriatic nail changes, progressive destruction of the distal interphalangeal joints of the hands and feet and a high incidence of sacro-iliac joint involvement. The results of serologic tests for rheumatoid factor are usually negative in the presence of psoriasis. 2. Rheumatoid (Ankylosing) Spondylitis (Table 1). rI'he earliest complaints of rheumatoid spondylitis may be morning stiffness and aching in the low back, aggravated by coughing, sneezing, deep breathing or straining. Symptoms may be intermittent at first and persistent later on. Early physical signs are disappearance of the normal lumbar curve, and diminished chest expansion and total vital capacity. Roentgenograms of the lower back, including the sacro-iliac joints, will reveal characteristic changes of sacro-iliac arthritis in 98 per cent of patients. However, these changes may not be present for the first few years of the disease. The sedimentation rate may be normal in about 20 per cent of patients and the serologic tests for rheumatoid factor are almost invariably negative. 3. Arthritis Associated with Enteropathies. Articular symptoms occur in about 20 per cent of patients with chronic ulcerative colitis. In our experience, five types of articular problems are recognizable: classical

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rheumatoid arthritis, rheumatoid spondylitis (the most common form), nonspecific arthralgias, erythema nodosum (which almost always is accompanied by arthralgia and actual synovitis), and "acute toxic arthritis." The arthritis is recurrent, mild, and migratory, with the knees and ankles being involved most frequently. Medical or surgical control of the colitis may bring about a remission in the nonspecific arthralgias, the erythema nodosum and the "acute toxic arthritis," but not in the well-established rheumatoid arthritis or spondylitis. 1-'he serologic tests for rheumatoid factor almost invariably give negative results in all of these conditions. Other enteropathies associated with arthralgia at times are regional enteritis, steatorrhea and amebic and bacillary dysentery. 4. Palindromic Rheumatism. This is a condition manifested by some patients who have frequent attacks of acute, short-lived (several hours to several days) arthritis recurring at irregular intervals over a period of years without residual joint damage. There is some question about the true significance of this entity since many of these patients are simply manifesting an atypical form of gout, rheumatoid arthritis, or one of the other connective tissue disorders. One or two joints are affected at a time, usually the metacarpophalangeal joints, proximal interphalangeal joints, wrists, knees and ankles, and a true synovitis is evident at the time of an attack. l-'he onset of this condition is usually sudden, between the ages of 20 and 40; it is apparently uninfluenced by weather changes, and the sedimentation rate is usually normal. The results of serologic tests for rheumatoid factor may be positive in patients with this syndrome, alerting the physician to the fact that this may be an atypical form of rheunlatoid arthritis. Degenerative Joint Disease (Table 1)

Degenerative joint disease accounts for 25 to 30 per cent of all cases of arthralgia. It is a universal condition, but in men, dorsolumbar spine and hip symptoms predominate, whereas in women, cervical spine, hand and knee symptoms seem to be more frequent. Complete disappearance of symptoms for long intervals is unusual. r-rhe arthralgia is usually relieved or absent when the patient is at rest, but occasionally Inay awaken the patient from a sound sleep at night. Morning stiffness may be present but is usually localized to the symptomatic joint rather than generalized, as is the case in rheumatoid arthritis. A true synovitis with effusion may occur, particularly in weight-bearing joints such as the knee and ankle. Usually the erythrocyte sedimentation rate is normal but if a true synovitis exists in a joint it may be quite high. Roentgenograms of the affected joints show narrowing of the joint space, eburnation or condensation of the bone at the joint margin and frequently marginal overgrowth of bone or "spurs."

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Joint Trauma (Table 1)

In joint trauma the history is of paramount importance but it is important to remember that occasionally an attack of rheumatoid arthritis or gout seems to follow injury to a joint. Gout (Table 1)

Gout accounts for 3 to 5 per cent of all types of arthralgia. IJrecipitating factors may be surgery, trauma, systemic infections, allergens, emotional cl isturbances, dietary indiscretions including weight-reduction diet, unusual physical activities, and several drugs (sulfathiazole, vitamin B 12 , ergotamine, antibiotics, diuretics, liver extract, insulin, thiamine, .A.. CTH, etc.). Prodromal symptoms are occasionally found, such as craving for food, restlessness, irritability or a peculiar tingling or aching in the joint. The onset of the attack is usually sudden, often in the night or early morning, and the first attack affects the first metatarsophalangeal joint in 25 per cent of patients. The pain of the acute attack is usually excruciating, and incapacitation ensues about 12 to 48 hours after onset. There may be marked tenderness over the affected joint. After subsidence of the acute attack there are no residual synlptoms except perhaps in later years when chronic gouty arthritis with destruction of the joint surfaces has occurred. The response to colchicine is usually diagnostic and occurs within 12 to 24 hours. It has been reported, however, that the symptoms of arthritis associated with sarcoidosis also respond well to colchicine. Physical examination of the affected joint reveals extreme tenderness and reddish discoloration of the skin, sometimes giving the appearance of cellulitis. Desquamation of the skin over the affected joint may be seen as the attack subsides. T'Ihe presence of tophi should be sought but they may be absent early in the disease. They are found in the margins of the cars, the ankles, heels, tendons of the fingers, over the olecranon process and in the prepatellar bursa. During the acute attack the erythrocyte sedimentation rate is usually elevated and there may be leukocytosis, but the nlost important diagnostic feature is elevation of the serum uric acid which is found in about 95 per cent of patients. It should be remembered, however, that certain drugs, such as chlorothiazide, related diuretics and aspirin in small doses, can raise the serum uric acid level. I'Ihe typical punched-out, radiolucent areas of epiphysial bone which can be seen on the roentgenogram are usually not present in the early stages of the disease. Septic Arthritis

Suppuration in a joint may be caused by Staphylococcus aureus, alpha or beta hemolytic streptococcus, Jlseudomonas aeruginosa and E. coli, and less frequently by Salmonella, Vibrio, nlycotic infection, Ineningococcus and pneumococcus. Septic arthritis should be considered in all

The Differential Diagnosis of Arthralgia

517

cases of acute monarticular arthritis and may be accompanied by malaise and low grade fever. If this diagnosis is made or suspected, aspiration of the joint fluid is inlperative. The leukocyte count of synovial fluid is usually over 50,000 cells per cubic millimetcr, of which 90 per cent or more arc polymorphonuclear leukoeytes. Appropriate smears, cultures and sensitivity studies should be carried out. Psychogenic Rheumatism (l"able 1)

In psyehogenic rhelunatisln arthralgia is present in many or all of the joints. Characteristically, the pain is severe, constant and totally unaffected by treatment or environment. l"he physical examination reveals no articular or muscular disease, but may be remarkable for the presence of ubiquitous tenderness. Laboratory and radiologic studies are normal. Rheumatic Fever (Table 1)

A history of streptococcal infection two or three weeks preceding the onset is more commonly found in rheumatic fever than in any of the other conditions mentioned above. }1--'ever is usually higher than in rheumatoid arthritis and the subcutaneous nodules which are often found differ from rheumatoid nodules in that they are smaller and more rapidly evanescent. Electroeardiographic changes and a high or rising antistreptolysin titer may be of diagnostic aid. Acute rheumatic fever may respond to large doses of salicylates more dramatically than other arthralgias. Reiter's Syndrome (l"able 1)

Reiter's syndrome is characterized by a triad of arthritis, urethritis and conjunctivitis, but many patients have, in addition, dermatitis, balanitis, diarrhea, and lesions of the oral mucous membrane. The arthritis resembles rheumatoid arthritis but the usual attack lasts only weeks to months. rrhere may be recurrences over the years, however, and occasionally the arthritis becomes chronic. The urethral smear for gonococci is usually negative. Intermittent Hydrarthrosis

Intermittent hydrarthrosis consists of recurrent, relatively painless synovial effusions usually in one or both knees, lasting three to five days. Between attacks the patient is asymptomatic and there are no systemic manifestations. In some patients this is an atypical form of rheumatoid arthritis. Bursitis, Shoulder-Hand Syndrome, and So Forth (Table 1)

These conditions, including calcific tendinitis of the shoulders, bicipital tendinitis and fibrositis, are sometimes referred to as "nonarticular rheumatism." 1"ogether they comprise 10 to 20 per cent of all cases of arthralgia. Constitional symptoms are absent.

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ARNALDO (j. CAIlVALHO, LUIS Ji'ERNANDEZ-HERLIHY

CONDITIONS IN WHICH ARTHRALGIA MAY BE PROMINENT

Other Connective Tissue Disorders

Systemic lupus erythematosus is the only other connective tissue disorder in which arthralgia commonly dominates the clinical picture, and is sometimes clinically indistinguishable from rheumatoid arthritis. Arthralgia or arthritis occurs at sorne tirne in about 90 per cent of patients with systemic lupus erythematosus. It is the initial manifestation in about onc-third of patients, and is present at the onset of the illness along with other features of the disease in another third. The pain in the joints may be severe, but frequently objective findings of arthritis are absent in these cases. rrhe joint symptoms tend to be evanescent and migratory. Pleurisy with or without effusion occurs in over 50 per cent of patients. Laboratory aids in diagnosis are a positive L.E. clot test, positive fluorescent antibody test, false positive serologic test for syphilis and leukopenia. In polyarteritis nodosa, true arthritis is rare although arthralgias similar to those of systemic lupus erythematosus are not uncommon. Muscle biopsy may be diagnostic. l~he joint symptoms of dermatomyositis or polymyositis are similar to those of systemic lupus erythematosus, but in addition muscle weakness, atrophy and tenderness may be prominent, particularly in the proximal muscle groups, such as the shoulder and pelvic girdles. Skin lesions are not characteristic and may resemble almost any eruption. The sine qua non of diagnosis is skin and muscle biopsy. In scleroderma, arthralgias may be prominent but careful examination of the skin with regard to loss of elasticity and atrophy should leave little doubt as to diagnosis in most cases. W egener's granulomatosis is considered by some to be a form of polyarteritis nodosa and is characterized by necrotizing granulomatous lesions of the nasal passages, sinuses and respiratory tract, and generalized arteritis and focal glomerulitis. Arthralgias are occasionally present in variable forms in these patients. Arthropathy Associated with Malignant Disease

There has been increased awareness lately of the association between arthralgias, or apparent arthritis, and malignant disease. Perhaps the best recognized association is that of hypertrophic osteoarthropathy with cancer of the lung. Hypertrophic osteoarthropathy usually consists of a triad of clubbing of the fingers and toes, chronic periostitis with new bone formation at the distal end of long bones and arthritis, although all three are not necessarily present at the same time. Superficially it may resemble rheumatoid arthritis but frequently the hands and feet have an almost acromegalic appearance and it is evident that there is enlarge-

The Differential Diagnosis of Arthralgia

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ment not only over the joints but also along the shaft of the long bone. The tibias may be quite warm and tender to the touch. A roentgenogram of the hand may reveal changes similar to those of early rheumatoid arthritis, but the periosteum of the shaft of long bones, particularly the tibia and radius, may be thickened. Removal of the tumor may result in disappearance of the arthropathy. Arthralgias have also been described in some patients with leukemia, lymphoma, cancer of the breast, uterus, stomach, liver, pancreas, and intestine. Very rarely, a metastatic lesion may be found in a painful joint. Systemic Infections

Patients with tuberculosis, syphilis, brucellosis and subacute bacterial endocarditis frequently have arthralgias. A chronic monarthritis should be suspected of being tuberculous and a synovial biopsy and synovial fluid culture are frequently helpful in diagnosis. Gonococcal arthritis occurs 10 to 20 days after the onset of the genital disease. It usually begins as a migratory polyarthritis, soon becoming localized to one or two large joints. These are red, hot, swollen and extremely tender. This diagnosis should be suspected when acute arthritis occurs in the latter half of pregnancy and in the immediate postpartum period. Radiologically, destructive changes may appear rapidly. The gonococcus may be recovered from the synovial fluid and should always be looked for. Arthritis and arthralgias may occur in systemic fungous infections, such as coccidioidomycosis, actinomycosis, histoplasmosis and blastomyCOSIS.

Several viral infections may be accompanied or followed by joint manifestations, for instance, mumps, influenza, hepatitis, rubella and lymphogranuloma venereum. Arthralgias may follow immunizations and vaccination. In all of these instances the arthralgia rarely lasts more than two weeks. Sarcoidosis

Arthralgia is not an uncommon finding in sarcoidosis and 15 to 20 per cent of these patients have bone lesions demonstrable by roentgenogram. Involvement of the hands is suggestive, especially the middle and distal phalanges, and the metacarpal and metatarsal bones. The' rad~ologic picture may simulate that of gout, showing punched-out areas In the bone adjacent to the joint. Erythema Nodosum

This is an acute febrile illness with skin manifestations resembling large hives, usually occurring on the extremities and associated with arthralgia and malaise. It is more common in the winter and spring

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months. Joint swelling may be present. A roentgenogram of the chest may reveal hilar adenopathy indistinguishable from sarcoidosis with which erythema nodosum is, in fact, sometimes associated. Usually a slight leukocytosis and an elevation in the erythrocyte sedimentation rate are found. It is a self-limited illness but may recur. Serum Sickness 'rhis disease usually begins seven to 14 days after the exhibition of serum, sulfonamides or penicillin. Arthralgia is the presenting symptom in 50 per cent of the patients. The temporomandibular joint is frequently the first joint to be involved. 'fhere may be actual synovitis and, in addition, urticaria, pruritus, fever, proteinuria, eosinophilia and slight lymphadenopathy. Henoch-Schoenlein Purpura (Anaphylactoid Purpura) Henoch-Schoenlein purpura is a relatively rare condition occurring in children and adolescents. The knees and ankles are predominantly involved but there may be a migratory arthritis which usually subsides in two to three days. Accompanying features are purpuric or erythematous lesions and abdominal pain. The purpura may be absent, making the diagnosis difficult. The entire illness rarely lasts over a month. Sj ogren's Syndrome This syndrome is characterized by arthritis, keratoconjunctivitis sicca and salivary gland abnormality producing xerostomia. It may be seen in association with rheumatoid arthritis, polymyositis, polyarteritis nodosa, anaphylactoid purpura, lymphomas, sarcoidosis, systemic lupus erythematosus, thyroiditis or purpura hyperglobulinemica. CONDITIONS IN WHICH ARTHRALGIA OCCASIONALLY OCCURS

Arthralgia occasionally occurs in the following conditions: 1. Endocrinopathies: Acromegaly, myxedema, primary hyperparathyroidism 2. Heredofamilial Disorders: Hemophilia, sickle cell disease, ochronosis, Marfan's syndrome 3. Dysproteinemias 4. Diseases of Medical Progress: Hydralazine syndrome, postcommissurotomy syndrome 5. Diseases of Metabolism: Osteomalacia 6. Miscellaneous : Weber-Christian disease, Stevens-Johnson syndrome, polymyalgia rheumatica, Behget's syndrome SUMMARY

A classification of the diseases in which arthralgia can occur has been presented. Differential diagnosis of the most important of these has been

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discussed, stressing the value of a carefully taken history, the physical examination and the observation of the evolution of the arthralgia as diagnostic aids. In conclusion, it is well to remember that arthralgia may occur in almost any disease. SUGGESTED REFERENCES FOR READING 1. Coggeshall, H. C.: The significance and variation of pain in arthritis. M. CLIN. NORTH AMERICA 42: 1603-1611 (Nov.) 1958. 2. Editorial. Comments on the Fourteenth Rheumatism Review. Ann. Int. Med. 56: 807-810 (May) 1962. 3. Hollander, J. L. (Ed.): Arthritis and Allied Conditions: A Textbook of Rheumatology. 6th Ed. Philadelphia, Lea & Febiger, 1960. 4. Hollander, J. L. and Brown, E. M., Jr.: Diagnosis in arthritides. M. CLIN. NORTH AMERICA 35: 1749-1763 (Nov.) 1951. 5. Montgomery, M. M., Pilz, C. G. and Aronson, A. R.: Early diagnosis of arthritis and allied disorders. M. CLIN. NORTH AMERICA 44: 29-48 (Jan.) 1960. 6. Primer on the Rheumatic Diseases. Parts 11 and Ill. Prepared by Committee of the American Rheumatism Assn. J.A.M.A. 171: 1345-1356 (Nov. 7) and 1680-1691 (Nov. 21) 1959. 7. Rheumatism and Arthritis: Review of American and English Literature of Recent Years. Thirteenth Rheumatism Review. Ann. Int. Med. 53: 1-226 (Dec. 30) 1960. Fourteenth Rheumatism Review. Ann. Int. Med. 56: 1-152 (May) 1962. 8. Robinson, W. D.: The problem of diagnosis in arthritis. M. CLIN. NORTH AMERICA 45: 1117-1131 (Sept.) 1961.