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⇱ Nonarticular Rheumatism/Regional Pain Syndrome: Background, Etiology, Pathophysiology

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Nonarticular Rheumatism/Regional Pain Syndrome

Updated: Jan 16, 2026
  • Author: Paramarajan Piranavan, MBBS, FACR; Chief Editor: Herbert S Diamond, MD  more...
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Overview

Background

Nonarticular rheumatism/regional pain syndrome refers to a group of musculoskeletal pain syndromes that arise from soft tissues (such as muscles, ligaments, tendons, bursae, fascia) rather than the joints themselves. These conditions have no primary bone or synovial involvement. They can be broadly classified as follows [1, 2, 3] :

  • Nociceptive soft-tissue syndromes - Disorders, such as tendonitis, bursitis, and overuse syndromes, characterized by activation of nociceptors in soft tissues
  • Neuropathic compression/entrapment syndromes - Disorders, such as carpal tunnel and thoracic outlet syndromes, characterized by damage or compression to the peripheral nerves
  • Structural/biomechanical disorders - Disorders, such as flatfoot, characterized by abnormal anatomy that leads to increased mechanical stress
  • Regional myofascial and trigger point syndromes - Disorders, such as myofascial pain in the neck/shoulder/trapezius, characterized by soft tissue pain mediated by trigger points
  • Complex regional pain syndrome (CRPS) - Characterized by regional pain with autonomic, sensory, motor, and trophic abnormalities; there are two types, CRPS type I and CRPS type II
  • Generalized, or widespread, pain syndromes - Disorders, such as fibromyalgia syndrome, characterized by widespread, chronic pain resulting from central sensitization/nociplastic mechanisms
  • Mixed/overlap syndromes - Conditions, such as overuse tendinopathy with central sensitization, that combine two or more of the above components (nociceptive, neuropathic, structural, nociplastic)

The following articles provide additional information:

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Etiology

Nonarticular rheumatism arises from the interplay between a broad mix of factors. Some of the commonly implicated etiologies are summarized below.

Mechanical and overuse factors

Repetitive strain and microtrauma from occupational, athletic, or ergonomic strain alter the tendon collagen structure, promote matrix microtears, and predispose to tendinopathy and bursitis. [4]

Structural abnormalities (eg, flatfoot, limb-length discrepancy, scoliosis) alter force distribution across tendons, entheses, and bursae, increasing the risk of localized pain syndromes. [5]

Trauma

Falls, blows, or surgery can inflame bursae or provoke entrapment neuropathies through swelling or scar formation.

Metabolic and systemic conditions

Crystal deposition (calcium pyrophosphate, hydroxyapatite, monosodium urate [the latter found in gout]) can precipitate bursitis and tendonitis.

Endocrine/metabolic diseases (diabetes, hypothyroidism, acromegaly, amyloidosis, obesity) can weaken connective tissues, increasing the risk for bursal and tendon pathology. [6]

Drugs

Certain drugs such as fluoroquinolones (associated with tendinopathy and tendon rupture through oxidative stress and impaired tenocyte metabolism) and glucocorticoids (associated with tendon weakening) are implicated in soft tissue pathologies. [7]

Autoimmune and inflammatory associations

Enthesitis (inflammation of site of attachment of ligament or tendon to the bone) is a common finding in certain autoimmune conditions such as spondyloarthropathies and is driven by cytokine signaling via the interleukin-23 (IL-23)/IL-17 pathways. [8]

Peritendinous and bursal manifestations may occur as a part of systemic conditions such as rheumatoid arthritis and systemic lupus erythematosus (SLE).

Psychosocial stress

Chronic stress, sleep disturbance, and psychological trauma are recognized as strong risk factors for fibromyalgia and widespread pain. They contribute to central sensitization and hypothalamic-pituitary-adrenal (HPA)–axis dysregulation. [9]

Sex and hormones

Female sex (especially in midlife) confers higher risk of fibromyalgia, likely through neuroendocrine and genetic mechanisms. [10]

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Pathophysiology

The mechanism of pain can be broadly classified into nociceptive, neuropathic, and nociplastic, as follows:

  • Nociceptive pain - This is from actual tissue injury or degeneration, arising from inflammation or trauma; this type of pain is usually localized to the area of damage
  • Neuropathic pain - This results from damage to the nerves from various etiologies such as mechanical trauma, diabetic neuropathy, or medication; this type of pain is either localized or present in dermatomal distribution
  • Nociplastic pain - This arises from central sensitization and is characterized by dysfunction in the nervous system signaling pathways, with no obvious tissue damage; pain perception is amplified, and inhibitory pathways are impaired [1]

Tendinopathy

Tendinopathy represents a failed healing–degenerative continuum, in which repetitive loading produces matrix micro-damage, disorganized collagen (with an increase in type III collagen), neovascularization, and nerve ingrowth. These changes occur alongside variable inflammation and form the basis of the modern continuum model of tendinopathy. [4] Intratendinous pressure and local hypoxia further amplify pain and structural damage during loading. [11]

Certain medications, particularly fluoroquinolones, can precipitate tendinopathy through oxidative stress, altered matrix metalloproteinase (MMP) activity, and tenocyte dysfunction. The risk is dose- and age-dependent and worsens with concurrent steroid use, prompting a boxed warning from the US Food and Drug Administration (FDA) on fluoroquinolones. [7, 12]

Bursitis

Bursitis arises when synovial-lined bursae become inflamed due to repetitive friction, trauma, infection, crystal deposition, or nearby tendon disease.

Enthesopathy

Enthesopathy, particularly in spondyloarthritides, reflects the vulnerability of the enthesis organ to mechanical stress and micro-damage. These stresses trigger innate immune activation, and in conditions such as spondylarthritis, the IL-23/IL-17 cytokine axis drives inflammation, pain, and new bone formation in the form of enthesophytes and syndesmophytes. Experimental models further support the role of IL, as IL-23 overexpression alone can induce enthesitis and psoriatic arthritis–like changes. [8]

Myofascial pain syndrome

Myofascial pain syndrome is characterized by regional trigger points located within taut muscle bands. These trigger points exhibit abnormal end-plate activity and sensitized nociceptors. [13] Modern understanding frames myofascial pain syndrome as a combination of motor end-plate dysfunction and peripheral sensitization, with variable contribution from central amplification mechanisms. [14]

Entrapment and compression neuropathies

Entrapment and compression neuropathies, such as carpal tunnel or tarsal tunnel syndrome, occur when nerves are compressed within tight fibro-osseous tunnels. This leads to increased intraneural pressure, ischemia, focal demyelination, axonal dysfunction, and neuroinflammation, with chronic compression raising the risk of fibrotic changes. In carpal tunnel syndrome specifically, median nerve ischemia and demyelination correlate closely with the severity of conduction deficits and symptoms. [15]

CRPS

CRPS is a multifactorial condition marked by both peripheral and central sensitization, neurogenic inflammation with cytokine and neuropeptide release, immune mechanisms, alterations in small nerve fibers, and sympathetic dysregulation leading to vasomotor changes. Its clinical expression varies between early “warm” phases (with sweating, warmth, swelling, and inflammation) and later “cold” phases, reflecting evolving pathophysiology over time. [2]

Nociplastic pain syndromes

Finally, widespread nociplastic pain syndromes such as fibromyalgia are dominated by central sensitization, in which pain processing is amplified within the central nervous system (CNS) and descending inhibitory control is impaired. The International Association for the Study of Pain (IASP) has developed nociplastic pain criteria to help identify such cases, in which symptoms are disproportionate to identifiable tissue damage or neural injury. [16] A subset of patients also show small-fiber pathology, suggesting that peripheral factors may contribute in some individuals. Additionally, stress-system dysregulation, particularly of the HPA axis and autonomic system, along with neuroinflammation, underpins the links between pain hypersensitivity, poor sleep, mood disturbance, and fatigue in these disorders. [9]

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Epidemiology

Nonarticular rheumatic disorders represent some of the most common musculoskeletal complaints in primary care. A 2021 Global Burden of Disease (GBD) analysis estimated the global prevalence of musculoskeletal problems, not including osteoarthritis, rheumatoid arthritis, gout, low back pain, and neck pain, at 6320 per 100,000 population, with rates approximately 47% higher in females. Prevalence peaked in the 65-69 year age group. [17]

The following is a concise table that provides the most current epidemiologic data for some common nonarticular rheumatic conditions.

 Table 1. Epidemiology of Nonarticular Rheumatic Conditions

(Open Table in a new window)

Disorder (typical non-articular examples)

Global prevalence

Global incidence

US prevalence

US incidence

Shoulder pain (rotator-cuff–related/subacromial pain syndromes)

Point prevalence commonly 6-26% [18]

-

Older adults (≥65 y): ~20% report shoulder pain over their lifetime [19]

-

Rotator cuff tears/rotator cuff disease

~22% in general population [20]

-

Age >40 y: ~6.8-22.4% [21]

-

Lateral epicondylitis (tennis elbow)

Point prevalence ~1-3% in adults [22]

~3.0-3.4/1000 person-years [23]

-

~1.51/1000 person-years [24]

Carpal tunnel syndrome

Highly variable by definition; 14.4% [25]

-

-

-

Greater trochanteric pain syndrome (gluteal tendinopathy/trochanteric bursitis)

Population-level prevalence uncertain; in industrialized cities, estimates ~10-25% [26]

~1.8/1000 person-years in primary care [27]

Unilateral and bilateral: 15% and 8.5% in women (respectively), 6.6% and 1.9 % in men (respectively) [28]

-

Plantar fasciitis (plantar heel pain)

~11-15% of foot complaints [29]

-

-

-

Myofascial pain syndrome (regional myofascial pain with trigger points)

-

-

Rough estimate ~9 million people affected [30]

-

Fibromyalgia

~2–3% [31]

-

~1.75% [31]

-
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Prognosis

Localized conditions like tendinopathy, bursitis, and entrapment neuropathies usually have a good prognosis, especially when treated early with rest, physiotherapy, or injections. Most patients improve within months, though recurrence is common if risk factors (eg, repetitive strain, poor ergonomics) persist. Surgical outcomes for entrapments (like carpal tunnel) are generally favorable. [4]

Myofascial pain syndrome often responds to trigger point therapy and rehabilitation, but relapses are frequent unless posture and occupational triggers are corrected. [13]

CRPS carries a guarded prognosis; some patients resolve spontaneously, but up to one third remain chronically disabled despite treatment. Early mobilization and multidisciplinary care improve chances of recovery. [2]

Fibromyalgia generally follows a chronic, fluctuating course, with most patients experiencing persistent pain, fatigue, and impaired quality of life rather than full remission. Long-term studies show only about 10-25% of patients achieve meaningful improvement, while 30-40% worsen over time; the majority remain relatively stable but symptomatic. Predictors of better prognosis include younger age, shorter symptom duration, lower baseline severity, and absence of comorbid depression or anxiety, while early improvements in pain correlate with better long-term outcomes. Overall, fibromyalgia rarely resolves completely, but many patients can achieve partial improvement in pain, function, sleep, and quality of life with multimodal therapy and early intervention. [32]

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Patient Education

Resources for patient education include the following:

For additional patient education information, see Fibromyalgia, Chronic Pain, and Tennis Elbow (Lateral Epicondylitis).

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References

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  23. Shiri R, Viikari-Juntura E, Varonen H, Heliövaara M. Prevalence and determinants of lateral and medial epicondylitis: a population study. Am J Epidemiol. 2006 Dec 1. 164 (11):1065-74. [QxMD MEDLINE Link].

  24. Degen RM, Conti MS, Camp CL, Altchek DW, Dines JS, Werner BC. Epidemiology and Disease Burden of Lateral Epicondylitis in the USA: Analysis of 85,318 Patients. HSS J. 2018 Feb. 14 (1):9-14. [QxMD MEDLINE Link].[Full Text].

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Tables
Table 1

Disorder (typical non-articular examples)

Global prevalence

Global incidence

US prevalence

US incidence

Shoulder pain (rotator-cuff–related/subacromial pain syndromes)

Point prevalence commonly 6-26% [18]

-

Older adults (≥65 y): ~20% report shoulder pain over their lifetime [19]

-

Rotator cuff tears/rotator cuff disease

~22% in general population [20]

-

Age >40 y: ~6.8-22.4% [21]

-

Lateral epicondylitis (tennis elbow)

Point prevalence ~1-3% in adults [22]

~3.0-3.4/1000 person-years [23]

-

~1.51/1000 person-years [24]

Carpal tunnel syndrome

Highly variable by definition; 14.4% [25]

-

-

-

Greater trochanteric pain syndrome (gluteal tendinopathy/trochanteric bursitis)

Population-level prevalence uncertain; in industrialized cities, estimates ~10-25% [26]

~1.8/1000 person-years in primary care [27]

Unilateral and bilateral: 15% and 8.5% in women (respectively), 6.6% and 1.9 % in men (respectively) [28]

-

Plantar fasciitis (plantar heel pain)

~11-15% of foot complaints [29]

-

-

-

Myofascial pain syndrome (regional myofascial pain with trigger points)

-

-

Rough estimate ~9 million people affected [30]

-

Fibromyalgia

~2–3% [31]

-

~1.75% [31]

-
Contributor Information and Disclosures
Author

Paramarajan Piranavan, MBBS, FACR Assistant Professor, Program Director of Rheumatology Training, Chief of Rheumatology, Department of Medicine,University of Kentucky College of Medicine, UK HealthCare

Paramarajan Piranavan, MBBS, FACR is a member of the following medical societies: American College of Physicians, American College of Rheumatology

Disclosure: Nothing to disclose.

Coauthor(s)

Vijaya Prakash Aviraag, MBBS Fellow Physician, Department of Internal Medicine, Division of Rheumatology, University of Kentucky

Vijaya Prakash Aviraag, MBBS is a member of the following medical societies: American College of Physicians, American College of Rheumatology

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

Daniel Muller, MD, PhD Associate Professor of Medicine, Department of Medicine, Section of Rheumatology, University of Wisconsin School of Medicine and Public Health

Daniel Muller, MD, PhD is a member of the following medical societies: American Holistic Medical Association, American College of Physicians-American Society of Internal Medicine, American College of Rheumatology

Disclosure: Nothing to disclose.

Robert E Wolf, MD, PhD Professor Emeritus, Department of Medicine, Louisiana State University School of Medicine in Shreveport; Chief, Rheumatology Section, Medical Service, Overton Brooks Veterans Affairs Medical Center

Robert E Wolf, MD, PhD is a member of the following medical societies: American College of Rheumatology, Arthritis Foundation, Society for Leukocyte Biology

Disclosure: Nothing to disclose.

David Rabago, MD Assistant Professor, Co-Director, Primary Care Research Fellowship, Associate Research Director, Department of Family Medicine, University of Wisconsin School of Medicine and Public Health

David Rabago, MD is a member of the following medical societies: American Academy of Family Physicians, North American Primary Care Research Group, Society of Teachers of Family Medicine

Disclosure: Nothing to disclose.

T P Sudha Rao, MD Associate Professor of Medicine, Virginia Commonwealth University School of Medicine; Chief, Rheumatology Fellowship Coordinator, Department of Rheumatology, McGuire VA Medical Center

T P Sudha Rao, MD is a member of the following medical societies: American College of Rheumatology

Disclosure: Nothing to disclose.

Evan Dombrosky, MD Rheumatologist, Central Virginia VA Health System

Evan Dombrosky, MD is a member of the following medical societies: American College of Rheumatology

Disclosure: Nothing to disclose.

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