An abrupt onset of widespread musculoskeletal pain is commonly seen in primary care and specialty medicine. There are multiple potential causes for such pain, including brief self-limited disorders and life-threatening emergencies. This paper discusses the most common and important acute generalized musculoskeletal (MSK) pain scenarios, with five sample patient cases to illustrate helpful differential diagnostic features. For the purposes of this paper, acute refers to pain that is present for 4 weeks or less.

Determine Whether Inflammation Is Present

The most important factor in evaluating any patient with generalized MSK pain is to first determine whether there is associated inflammation. For instance, is the pain arthritis or arthralgia, myositis or myalgia? Such diagnoses can only be definitively determined with a careful and complete MSK examination.

Physical Exam

The cardinal signs of joint inflammation – swelling, redness, and heat – always indicate synovitis. Other helpful physical findings of inflammation include soft tissue swelling, joint tenderness on palpation, and loss of both active and passive joint range of motion. Often, especially early in the course of a systemic illness, the joint inflammation may be fleeting or subtle.

Swelling and inflammation involving the knees, fingers, and wrists tend to be the most recognizable. However, inflammation involving the hips, shoulders, neck, and back are not easily noted on physical examination.

Muscle inflammation is more difficult to detect on physical examination. Myositis seldom presents with overt signs of inflammation in the muscle. Myositis should be suspected in individuals with generalized myalgias and weakness, but the diagnosis rests on the physical finding of diffuse, proximal muscle weakness, confirmed with elevated muscle enzymes.

When joint or muscle inflammation is suspected but not accompanied by obvious inflammation on the MSK examination, laboratory tests may be the best clue that inflammation is present. The acute phase reactants, ESR and CRP, are almost always elevated in acute inflammatory disorders. They quickly increase in any inflammatory MSK disorder, although they will not aid in differential diagnosis.

Acute phase reactants, especially the CRP, may increase with obesity, but very elevated levels are rare.¹ Myositis is always associated with elevated muscle enzymes, particularly the creatine phosphokinase (CPK). In contrast, widespread muscle pain, characteristic of fibromyalgia, is not associated with muscle weakness, elevated muscle enzymes, or elevated acute phase reactants.

Rule Out Infection

Any patient presenting with acute generalized MSK symptoms should be evaluated as quickly as possible. If there is an associated fever, an acute infection must be excluded (see Table I). If a joint effusion is present, joint aspiration and synovial fluid analysis should be done on an emergent basis.

Table I: Acute MSK Pain and Fever: Most Common Infections to Rule Out.
Infection/Disease Identifying Clinical Features Tests
Hepatitis Small joint polyarthritis, rash Hepatitis A, C serology, LFTs
Parvovirus Large joint inflammation Parvovirus serology
DGI Polyarthritis, tenosynovitis, skin lesions Blood, GU cultures
Lyme disease Polyarthralgia, myalgia, ECM rash Lyme serology
DGI is disseminated gonococcal infection, GU is genitourinary, ECM is erythema chronicum migrans, LFTs is liver function tests

Diffuse MSK pain is occasionally associated with rubella and rubella vaccine, hepatitis A, and HIV. Viral serologic tests and liver function tests will usually be diagnostic of these disorders. Most types of bacterial arthritis involve a single joint but disseminated gonococcal infection (DGI) typically presents with polyarthritis, tenosynovitis, and skin lesions (see Table I). The skin lesions may be maculo-papular, pustular, or vesicular. The initial manifestations of Lyme disease (stage 1) at the time when the characteristic erythema migrans rash is noted, include fever, diffuse arthralgias, and myalgias, but joint swelling is rare in early Lyme disease. If untreated, late-stage Lyme disease may subsequently present with a single joint arthritis, usually the knee, but polyarthritis is rare.

In most patients with generalized MSK pain, symptoms begin more gradually, over a few weeks, and significant fever is unusual. However, every rheumatic disease – including rheumatoid arthritis, polymyalgia rheumatica, systemic lupus erythematosus (SLE), and vasculitis – may present for the first time acutely and with intense symptoms. In these cases, there is a broad differential diagnosis (see Table II).

Table II: Differential Diagnosis of Generalized MSK Pain.
Condition Identifying Clinical Features Testing
Rheumatoid Arthritis Small joint polyarthritis ESR/CRP, RF, anti-CCP
Polymyalgia Rheumatica Older patient, temporal arteritis ESR/CRP
Systemic Lupus Erythematosus Rash, Raynaud’s, hair loss ESR/CRP, ANA, urinalysis
Spondyloarthropathy Back and neck pain, decreased mobility ESR/CRP, x-rays, imaging, HLA-B27
Myositis Proximal muscle weakness, rash, statins Muscle enzymes
Cancer or paraneoplastic Bone pain, weight loss, fever, medications CBC, ESR/CRP
Endocrine disorder Weight gain, constipation TSH
ESR is erythrocyte sedimentation rate, CRP is C-reactive protein, RF is rheumatoid factor, anti-CCP is anti-cyclic citrullinated peptide, ANA is antinuclear antibody, HLA-B27 is human leucocyte antigen-B27, TSH is thyroid stimulating hormone

Rheumatoid Arthritis

Approximately 10% to 20% of people with a systemic rheumatic disease will present with generalized MSK pain over a matter of days or a few weeks.³ The most common rheumatic disease presenting with subacute widespread pain is rheumatoid arthritis. Rheumatoid arthritis usually begins with small joint polyarthritis, involving the fingers, wrists, knees, and feet. A rheumatoid factor and anti-CCP antibodies are present in most patients, but joint radiographs at this early stage are likely to be unrevealing.

Polymyalgia Rheumatica

Demographic features are usually not very helpful in rheumatic differential diagnosis since rheumatic inflammatory disorders, as well as fibromyalgia, are more common in younger women. However, polymyalgia rheumatica almost always begins after age 60 years. Polymyalgia rheumatica usually presents with myalgias and arthralgias involving the neck, shoulders, hips, and thighs. Arthritis and muscle weakness are absent, but patients complain of severe stiffness. Joint swelling is unusual. The association of giant cell arteritis must be kept in mind and patients should be asked about any new onset severe headaches, visual symptoms, or scalp tenderness. Acute phase reactants are usually markedly elevated.

Systemic lupus erythematosus may also present acutely with polyarthralgia or polyarthritis, involving both small and large joints. Other features of SLE at this initial stage often include facial skin rash, hair loss, photosensitivity, and Raynaud’s phenomena. The antinuclear antibody (ANA) is almost always positive, even in very early-onset SLE. Renal involvement is common, and a urinalysis and serum creatinine should be obtained.


Although back and neck pain are the characteristic features of the axial spondyloarthropathies, patients may present with diffuse MSK pain, including small and large joint polyarthritis. This is most common in psoriatic arthritis (PsA) but also characteristic of adult-onset juvenile rheumatoid arthritis (JRA). Adult-onset JRA and Reiter’s disease are commonly present with abrupt-onset polyarthritis, fever, rash, and oral lesions. Spinal x-rays and imaging, as well as the presence of HLA-B27 marker, may provide clues to the diagnosis.

Crystal-induced Arthritis

Crystal-induced arthritis (eg, gout and pseudogout) rarely presents initially with polyarthritis. However, patients with a preexisting history of gout or pseudogout may occasionally develop an acute polyarthritis.

There is a long list of medications capable of causing generalized MSK pain, but statins are the most important to consider. Most often statins are associated with non-specific myalgias and arthralgias. However, the less common occurrence of an acute or subacute myositis must be considered and muscle enzymes should always be obtained in any patient on statins who develops new, generalized MSK symptoms, especially if the physical examination demonstrates proximal muscle weakness.

Cancer and Endocrine Disorders

Individuals with cancer may rarely present with widespread MSK pain, although bone pain is usually confined to one or two areas. Weight loss, loss of appetite, and low-grade fever are often present. Paraneoplastic syndromes and immune reactions to immune modulators used to treat cancer, such as check point inhibitors, may present with diffuse polyarthralgia, myalgia, and polyarthritis. Immune checkpoint inhibitor-associated arthritis, caused by anti-PD1 or anti-PDL1 medicines, most often presents with a subacute RA-like picture.⁴

Case Examples: Test Your Clinical Skills

For each hypothetical case scenario, make a presumptive diagnosis and consider your decision regarding how to obtain further information such as laboratory testing. Then click SUBMIT and compare your choices to the clinical determinations made for each case.

Case 1

A 45-year-old female presents with a 2-week history of pain in her hands, knees, and feet, exhaustion, and loss of appetite. In the past week, she has been unable to take a walk or take care of her children. On examination, her joints demonstrate swelling and warmth involving her fingers, wrists, and knees. There is no rash and the examination of her heart and lungs is normal.

Case 2

A 70-year-old male describes severe aches and pains in the neck, shoulders, lower back, and hips for the past week. He has extreme difficulty getting out of bed or dressing himself and for the past few days has had intermittent low-grade fever. His past medical history includes hypertension and hyperlipidemia, and his medications include a diuretic and a statin, but the medications and doses have not changed during the past few years. The MSK physical examination demonstrates no obvious joint swelling or tenderness but decreased range of motion in the neck and shoulders. There is no significant muscle weakness or neurologic abnormality.

Case 3

A 29-year-old male presents with 3 days of widespread joint and muscle pain throughout his body and a diffuse skin rash over the trunk and extremities. He had been traveling out of the country during the previous month. For the past 2 days, he reports having a fever and loss of appetite. On examination, the temperature is 100.2, there is no definite joint swelling, but he is tender over the joints and soft tissues. There is a maculo-papular rash over the trunk, back, and extremities. There is no obvious weakness or neurologic abnormalities.

Case 4

A 45-year-old female presents with widespread muscle and joint pain during the past few weeks. She also feels exhausted, and the pain has kept her from sleeping. Her past medical history is unremarkable other than frequent headaches, which have also worsened in the past few weeks. On physical examination, there is no joint or muscle inflammation, but she is tender to palpation over the joints, muscles, and tendons in the neck, shoulders, arms, and hips.

Case 5

A 68-year-old female describes widespread pain, especially in her low back and right upper arm for the past month. Her appetite has been poor, and she has lost 10 pounds during that month. She has a history of obesity and adult-onset diabetes and is taking glucagon. The examination demonstrates bony hypertrophy of distal finger joints but no obvious swelling. She has a marked decreased range of motion in the lower back and right shoulder and is tender over the right upper arm.

Practical Takeaways

When evaluating an adult with recently onset, acute, generalized MSK pain, the first step is to determine whether inflammation is present, and, if so, whether there is evidence for arthritis or myositis. If fever and any systemic signs or symptoms are also noted, it is essential to exclude an infectious cause of the MSK pain on an emergent basis. Using a complete medical history and MSK examination, along with select laboratory tests, the differential diagnosis for acute widespread pain can be quickly narrowed down to a few general categories.

  1. Sharma A, Kumar A, Jha A, Agarwal A, Misra A. The impact of obesity on inflammatory markers used in the assessment of disease activity in rheumatoid arthritis – a cross-sectional study. Reumatologia. 2020;58(1):9-14. doi:10.5114/reum.2020.93506
  2. Marks M, Marks JL. Viral arthritis. Clin Med (Lond). 2016;16(2):129-134. doi:10.7861/clinmedicine.16-2-129
  3. El-Gabalawy HS, Duray P, Goldbach-Mansky R. Evaluating patients with arthritis of recent onset: studies in pathogenesis and prognosis. JAMA. 2000;284(18):2368-2373. doi:10.1001/jama.284.18.2368
  4. Ghosh N, Tiongson MD, Stewart C, et al. Checkpoint Inhibitor-Associated Arthritis: A Systematic Review of Case Reports and Case Series. J Clin Rheumatol. 2021;27(8):e317-e322.