Individuals affected by RS3PE typically have repeated episodes of inflammation of the lining of their synovial joints and swelling of the end portion of the limbs. The arms and hands are more commonly affected than the legs and feet. Both sides are usually involved though RS3PE can affect only one side in certain cases.

RS3PE is a constellation of symptoms that can be caused by many other conditions. Since there is no definitive diagnostic test, other conditions have to be ruled out before this rare condition can be diagnosed.

The main differential diagnosis is polymyalgia rheumatica (PMR), although pain, stiffness and weakness at the level of the shoulders and pelvic girdle with associated systemic symptoms (fever, malaise, fatigue, weight loss) is more typical of PMR. Prospective studies have found a subgroup of PMR patients with hand edema, as well as other similarities. Thus, RS3PE has been proposed as a condition related to PMR or even that they are both part of the same disorder. However, PMR typically requires protracted courses of steroids, whereas corticosteroids can be tapered more quickly with persisting remission in RS3PE.

Other rheumatological disorders that can cause the features typical for RS3PE include late onset (seronegative) rheumatoid arthritis, acute sarcoidosis, ankylosing spondylitis and other spondyloarthropathies such as psoriatic arthropathy, mixed connective tissue disease, chondrocalcinosis and arthropathy due to amyloidosis.

RS3PE has been documented in patients with cancers (Non-Hodgkin's lymphoma, gastric cancer, pancreatic cancer, lung cancer, breast cancer, colon cancer, prostate cancer and bladder cancer, among others), in whom it might represent a paraneoplastic manifestation.

Other underlying disorders include vasculitides such as polyarteritis nodosa.

Other causes of edema include heart failure, hypoalbuminemia, nephrotic syndrome and venous stasis. The key distinguishing feature is that these conditions don't tend to manifest with pitting edema at the back of the hands.

Symptoms of JIA are often nonspecific initially, and include lethargy, reduced physical activity, and poor appetite. The first manifestation, particularly in young children, may be limping. Children may also become quite ill, presenting with flu-like symptoms that persist. The cardinal clinical feature is persistent swelling of the affected joint(s), which commonly include the knee, ankle, wrist, and small joints of the hands and feet. Swelling may be difficult to detect clinically, especially for joints such as those of the spine, sacroiliac joints, shoulder, hip, and jaw, where imaging techniques such as ultrasound or MRI are very useful.

Pain is an important symptom. Morning stiffness that improves later in the day is a common feature (this implies inflammatory-type joint pain versus mechanical-type joint pain). Late effects of arthritis include joint contracture (stiff, bent joint due to fibrosis) and joint damage. Children with JIA vary in the degree to which they are affected by particular symptoms. Symptoms may also differ between sexes, affecting girls and boys differently among different geographic locations. This is predicted to be due to biological differences in different geographic regions. Children may also have swollen joints (inflammatory swelling, or in chronic arthritis due to synovial proliferation and thickening, and periarticular soft-tissue swelling).

Eye disease: JIA is associated with inflammation in the front of the eye (specifically iridocyclitis, a form of chronic anterior uveitis), which affects about one child in five who has JIA, most commonly girls. This complication is usually asymptomatic and can be detected by an experienced optometrist or ophthalmologist using a slit lamp. Later slit lamp features include synechiae. Most children with JIA are enrolled in a regular slit lamp screening program, as poorly controlled chronic anterior uveitis may result in permanent eye damage, including blindness.

Growth disturbance: Children with JIA may have reduced overall rate of growth, especially if the disease involves many joints or other body systems. Paradoxically, individually affected large joints (such as the knee) may grow faster, due to inflammation-induced increased blood supply to the bone growth plates situated near the joints. This can result in leg length discrepancy, and also deformities such as genu valgum. Asymmetrical growth can also affect other bones e.g. discrepancy in digit length. Marked differences in bone age (skeletal maturation) may be seen.

In general, pigmented villonodular synovitis often manifests initially as sudden onset, unexplained joint swelling and pain; the joint swelling is disproportionate to the amount of pain the patient feels at first. Decreased motion and increased pain occur as the disorder progresses as well as locking of the joint. The localized form often manifests initially as a painless, slow-growing mass and progresses to the other common symptoms of PVNS. The swelling often feels warm to the touch. Diffuse PVNS symptoms are often confused with those of Rheumatoid arthritis. While pigmented villonodular synovitis can occur in both pediatric and geriatric patients, it is more common with ages 20–50.

PVNS is locally aggressive and can spread to surrounding tissues, causing bone erosion and tissue damage. If not treated early, it can spread to areas outside the joint, and potentially cause permanent loss of range as well as intense pain. The disorder also has, on average, a 45% rate of recurrence.

Synovitis causes joint tenderness or pain, swelling and hard lumps, called nodules. When associated with rheumatoid arthritis, swelling is a better indicator than tenderness.

Transient synovitis causes pain in the hip, thigh, groin or knee on the affected side. There may be a limp (or abnormal crawling in infants) with or without pain. In small infants, the presenting complaint can be unexplained crying (for example, when changing a diaper). The condition is nearly always limited to one side. The pain and limp can range from mild to severe.

Some children may have a slightly raised temperature; high fever and general malaise point to other, more serious conditions. On clinical examination, the child typically holds the hip slightly bent, turned outwards and away from the middle line (flexion, external rotation and abduction). Active and passive movements may be limited because of pain, especially abduction and internal rotation. The hip can be tender to palpation. The log roll test involves gently rotating the entire lower limb inwards and outwards with the patient on his back, to check when muscle guarding occurs. The unaffected hip and the knees, ankles, feet and spine are found to be normal.

Clutton's joints is a term describing the finding of symmetrical joint swelling seen in patients with congenital syphilis. It most commonly affects the knees, presenting with synovitis and joint effusions (collections of fluid within the joint capsules) lasting up to a year. It has also been reported affecting the ankles, elbows, wrists and fingers. It is usually painless, although pain in the absence of trauma can occur in a few cases. There is usually no disability associated with the joint swelling, and recovery is usually complete. It occurs between 5 and 20 years of age in both sexes.

The condition was described in 1886 by Henry Hugh Clutton in "The Lancet".

SAPHO syndrome includes a variety of inflammatory bone disorders that may be associated with skin changes. These diseases share some clinical, radiologic, and pathologic characteristics.

An entity initially known as chronic recurrent multifocal osteomyelitis (CRMO) was first described in 1972. Subsequently, in 1978, several cases of CRMO were associated with blisters on the palms and soles (palmoplantar pustulosis). Since then, a number of associations between skin conditions and osteoarticular disorders have been reported under a variety of names, including sternocostoclavicular hyperostosis, pustulotic arthro-osteitis, and acne-associated spondyloarthropathy. The term SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) was coined in 1987 to represent this spectrum of inflammatory bone disorders that may or may not be associated with dermatologic pathology.

The definition is Synovitis Acne (commonly involving the face and upper back) Pustulosis Hyperostosis Osteitis

The rheumatoid nodule, which is sometimes in the skin, is the most common non-joint feature and occurs in 30% of people who have RA. It is a type of inflammatory reaction known to pathologists as a "necrotizing granuloma". The initial pathologic process in nodule formation is unknown but may be essentially the same as the synovitis, since similar structural features occur in both. The nodule has a central area of fibrinoid necrosis that may be fissured and which corresponds to the fibrin-rich necrotic material found in and around an affected synovial space. Surrounding the necrosis is a layer of palisading macrophages and fibroblasts, corresponding to the intimal layer in synovium and a cuff of connective tissue containing clusters of lymphocytes and plasma cells, corresponding to the subintimal zone in synovitis. The typical rheumatoid nodule may be a few millimetres to a few centimetres in diameter and is usually found over bony prominences, such as the elbow, the heel, the knuckles, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF (rheumatoid factor) titer, ACPA, and severe erosive arthritis. Rarely, these can occur in internal organs or at diverse sites on the body.

Several forms of vasculitis occur in RA, but are mostly seen with long-standing and untreated disease. The most common presentation is due to involvement of small- and medium-sized vessels. Rheumatoid vasculitis can thus commonly present with skin ulceration and vasculitic nerve infarction known as mononeuritis multiplex.

Other, rather rare, skin associated symptoms include pyoderma gangrenosum, Sweet's syndrome, drug reactions, erythema nodosum, lobe panniculitis, atrophy of finger skin, palmar erythema, and skin fragility (often worsened by corticosteroid use).

Synovitis is the medical term for inflammation of the synovial membrane. This membrane lines joints that possess cavities, known as synovial joints. The condition is usually painful, particularly when the joint is moved. The joint usually swells due to synovial fluid collection.

Synovitis may occur in association with arthritis as well as lupus, gout, and other conditions. Synovitis is more commonly found in rheumatoid arthritis than in other forms of arthritis, and can thus serve as a distinguishing factor, although it is also present in many joints affected with osteoarthritis. Long term occurrence of synovitis can result in degeneration of the joint.

Arthritis of joints involves inflammation of the synovial membrane. Joints become swollen, tender and warm, and stiffness limits their movement. With time, multiple joints are affected (polyarthritis). Most commonly involved are the small joints of the hands, feet and cervical spine, but larger joints like the shoulder and knee can also be involved. Synovitis can lead to tethering of tissue with loss of movement and erosion of the joint surface causing deformity and loss of function.

RA typically manifests with signs of inflammation, with the affected joints being swollen, warm, painful and stiff, particularly early in the morning on waking or following prolonged inactivity. Increased stiffness early in the morning is often a prominent feature of the disease and typically lasts for more than an hour. Gentle movements may relieve symptoms in early stages of the disease. These signs help distinguish rheumatoid from non-inflammatory problems of the joints, such as osteoarthritis. In arthritis of non-inflammatory causes, signs of inflammation and early morning stiffness are less prominent with stiffness typically less than one hour, and movements induce pain caused by mechanical arthritis.

The pain associated with RA is induced at the site of inflammation and classified as nociceptive as opposed to neuropathic. The joints are often affected in a fairly symmetrical fashion, although this is not specific, and the initial presentation may be asymmetrical.

As the pathology progresses the inflammatory activity leads to tendon tethering and erosion and destruction of the joint surface, which impairs range of movement and leads to deformity. The fingers may suffer from almost any deformity depending on which joints are most involved. Specific deformities, which also occur in osteoarthritis, include ulnar deviation, boutonniere deformity (also "buttonhole deformity", flexion of proximal interphalangeal joint and extension of distal interphalangeal joint of the hand), swan neck deformity (hyperextension at proximal interphalangeal joint and flexion at distal interphalangeal joint) and "Z-thumb." "Z-thumb" or "Z-deformity" consists of hyperextension of the interphalangeal joint, fixed flexion and subluxation of the metacarpophalangeal joint and gives a "Z" appearance to the thumb. The hammer toe deformity may be seen. In the worst case, joints are known as arthritis mutilans due to the mutilating nature of the deformities.

For a person with arthritis mutilans in the hands, the fingers become shortened by arthritis, and the shortening may become severe enough that the hand looks paw-like, with the first deformity occurring at the interphalangeal and metacarpophalangeal joints. The excess skin from the shortening of the phalanx bones becomes folded transversely, as if retracted into one another like opera glasses, hence the description "la main en lorgnette". As the condition worsens, luxation, phalangeal and metacarpal bone absorption, and skeletal architecture loss in the fingers occurs.

Pain in or around the hip and/or limp in children can be due to a large number of conditions. Septic arthritis (a bacterial infection of the joint) is the most important differential diagnosis, because it can quickly cause irreversible damage to the hip joint. Fever, raised inflammatory markers on blood tests and severe symptoms (inability to bear weight, pronounced muscle guarding) all point to septic arthritis, but a high index of suspicion remains necessary even if these are not present. Osteomyelitis (infection of the bone tissue) can also cause pain and limp.

Bone fractures, such as a toddler's fracture (spiral fracture of the shin bone), can also cause pain and limp, but are uncommon around the hip joint. Soft tissue injuries can be evident when bruises are present. Muscle or ligament injuries can be contracted during heavy physical activity —however, it is important not to miss a slipped upper femoral epiphysis. Avascular necrosis of the femoral head (Legg-Calvé-Perthes disease) typically occurs in children aged 4–8, and is also more common in boys. There may be an effusion on ultrasound, similar to transient synovitis.

Neurological conditions can also present with a limp. If developmental dysplasia of the hip is missed early in life, it can come to attention later in this way. Pain in the groin can also be caused by diseases of the organs in the abdomen (such as a psoas abscess) or by testicular disease. Rarely, there is an underlying rheumatic condition (juvenile idiopathic arthritis, Lyme arthritis, gonococcal arthritis, ...) or bone tumour.

Pain, swelling, or stiffness in one or more joints is commonly present in psoriatic arthritis. Psoriatic arthritis is inflammatory, and affected joints are generally red or warm to the touch. Asymmetrical oligoarthritis, defined as inflammation affecting one to four joints during the first six months of disease, is present in 70% of cases. However, in 15% of cases, the arthritis is symmetrical. The joints of the hand that is involved in psoriasis are the proximal interphalangeal (PIP), the distal interphalangeal (DIP), the metacarpophalangeal (MCP), and the wrist. Involvement of the distal interphalangeal joints (DIP) is a characteristic feature and is present in 15% of cases.

In addition to affecting the joints of the hands and wrists, psoriatic arthritis may affect the fingers, nails, and skin. Sausage-like swelling in the fingers or toes, known as dactylitis, may occur. Psoriasis can also cause changes to the nails, such as pitting or separation from the nail bed, onycholysis, hyperkeratosis under the nails, and horizontal ridging. Psoriasis classically presents with scaly skin lesions, which are most commonly seen over extensor surfaces such as the scalp, natal cleft and umbilicus.

In psoriatic arthritis, pain can occur in the area of the sacrum (the lower back, above the tailbone), as a result of sacroiliitis or spondylitis, which is present in 40% of cases. Pain can occur in and around the feet and ankles, especially enthesitis in the Achilles tendon (inflammation of the Achilles tendon where it inserts into the bone) or plantar fasciitis in the sole of the foot.

Along with the above-noted pain and inflammation, there is extreme exhaustion that does not go away with adequate rest. The exhaustion may last for days or weeks without abatement. Psoriatic arthritis may remain mild or may progress to more destructive joint disease. Periods of active disease, or flares, will typically alternate with periods of remission. In severe forms, psoriatic arthritis may progress to arthritis mutilans which on X-ray gives a "pencil-in-cup" appearance.

Because prolonged inflammation can lead to joint damage, early diagnosis and treatment to slow or prevent joint damage is recommended.

There are five main types of psoriatic arthritis:

- Oligoarticular: This type affects around 70% of patients and is generally mild. This type does not occur in the same joints on both sides of the body and usually only involves fewer than 3 joints.

- Polyarticular: This type accounts for around 25% of cases, and affects five or more joints on both sides of the body simultaneously. This type is most similar to rheumatoid arthritis and is disabling in around 50% of all cases.

- Arthritis mutilans (): Affects less than 5% of patients and is a severe, deforming and destructive arthritis. This condition can progress over months or years causing severe joint damage. Arthritis mutilans has also been called chronic absorptive arthritis, and may be seen in rheumatoid arthritis as well.

- Spondyloarthritis (): This type is characterized by stiffness of the neck or the sacroiliac joint of the spine, but can also affect the hands and feet, in a similar fashion to symmetric arthritis.

- Distal interphalangeal predominant (): This type of psoriatic arthritis is found in about 5% of patients, and is characterized by inflammation and stiffness in the joints nearest to the ends of the fingers and toes. Nail changes are often marked.

The most common symptoms are diarrhea, abdominal pain, weight loss, and joint pains. The joint pains may be due to migratory non-deforming arthritis, which may occur many years before any digestive tract symptoms develop; they tend to involve the large joints but can occur in any pattern and tend not to damage the joint surface to the point that the joint becomes deformed. Fever and chills occur in a small proportion of people.

In its more advanced form, malabsorption (insufficient absorption of nutrients from the diet) leads to wasting and the enlargement of lymph nodes in the abdomen. Neurological symptoms (discussed below) are more common in those with the severe form of the abdominal disease. Chronic malabsorptive diarrhea leads to the poor absorption of fat, causing steatorrhea (fatty, offensive stool), flatulence, and abdominal distension. Protein-losing enteropathy may also occur, causing depletion of albumin, a blood protein, which may lead to peripheral edema caused by the lowered oncotic pressures.

Hyperpigmentation of the skin occurs in almost half; some also have skin nodules. Various eye problems, such as uveitis, may occur; this is typically associated with deteriorating vision and pain in the affected eye. Endocarditis (infection of the heart valve) has been reported in a small number of cases, sometimes in people with no other symptoms of Whipple's disease; this is typically noticed as breathlessness and leg swelling due to fluid accumulation as the heart is unable to pump fluid through the body.

Of those affected by Whipple's disease, 10–40% of people have problems related to the involvement of the brain; the symptoms relate to the part of the brain that is affected. The most common problems are dementia, memory loss, confusion, and decreased level of consciousness. Eye movement disturbances and myorhythmia (rapidly repetitive movements of the muscles) of the face, together referred to as "oculomasticatory myorhythmia", are highly characteristic for Whipple's disease. Weakness and poor coordination of part of the body, headaches, seizures, as well as a number of more uncommon neurological features, are present in some cases.

Potential signs and symptoms include:

- Cardiovascular: Raynaud's phenomenon (is the presenting symptom in 30% of affected persons, occurs in 95% of affected individuals at some time during their illness); healed pitting ulcers on the fingertips; skin and mucousal telangiectasis; palpitations, irregular heart rate and fainting due to conduction abnormalities, hypertension and congestive heart failure.

- Digestive: gastroesophageal reflux disease, bloating, indigestion, loss of appetite, diarrhoea alternating with constipation, sicca syndrome and its complications, loosening of teeth and hoarseness (due to acid reflux).

- Pulmonary: progressive worsening of shortness of breath, chest pain (due to pulmonary artery hypertension) and dry, persistent cough due to interstitial lung disease.

- Musculoskeletal: joint, muscle aches, loss of joint range of motion, carpal tunnel syndrome and muscle weakness.

- Genitourinary: erectile dysfunction, dyspareunia, scleroderma renal crises and kidney failure.

- Other: facial pain due to trigeminal neuralgia, hand paresthesias, headache, stroke, fatigue, calcinosis and weight loss.

The signs and symptoms of POEMS syndrome are highly variable. This often leads to long delays (e.g. 13–18 months) between the onset of initial symptoms and diagnosis. In addition to the signs and symptoms indicated by the POEMS acronym, the PEST acronym is used to describe some of the other signs and symptoms of the disease. PEST stands for Papilledema, evidence of Extravascular volume overload (ascites, pleural effusion, pericardial effusion, and lower extremity edema), Sclerotic bone lesions, and Thrombocytosis/erythrocytosis (i.e. increased in blood platelets and red blood cells). Other features of the disease include a tendency toward leukocytosis, blood clot formation, abnormal lung function (restrictive lung disease, pulmonary hypertension, and impaired lung diffusion capacity), very high blood levels of the cytokine vascular endothelial growth factor (VEGF), and an overlap with the signs and symptoms of multicentric Castleman disease.

Peripheral arthritis has been reported in 92% of cases of SAPHO as well.

In children, the SAPHO syndrome is most likely to affect the metaphysis of long bones in the legs (tibia, femur, fibula), followed by clavicles and spine.

Signs and symptoms may include:

- Persistent or recurrent enlargement of the lips, causing them to protrude. If recurrent, the interval during which the lips are enlarged may be weeks or months. The enlargement can cause midline fissuring of the lip ("median cheilitis") or angular cheilitis (sores at the corner of the mouth). The swelling is non-pitting (c.f. pitting edema) and feels soft or rubbery on palpation. The mucous membrane of the lip may be erythemaous (red) and granular. One or both lips may be affected.

- Oral ulceration (mouth ulcers) which may be aphthous like, or be more chronic and deep with raised margins. Alternatively, lesions similar to pyostomatitis vegetans may occur in OFG, but this is uncommon.

- "Full width" gingivitis (compare with marginal gingivitis).

- Gingival enlargement (swelling of the gums).

- Fissured tongue (grooves in the tongue).

- Enlargement of the mucous membrane of the mouth, which may be associated with cobblestoning and mucosal tags (similar lesions often occur on the intestinal mucosa in Crohn's disease).

- Enlargement of the perioral and periorbital soft tissues (the tissues of the face around the mouth and the eyes). The facial skin may be dry, exfoliative (flaking) or erythematous.

- Cervical lymphadenopathy (enlarged lymph nodes in the neck).

- Facial palsy (weakness and altered sensation of the face).

The enlargement of the tissues of the mouth, lips and face seen in OFG is painless. Melkersson-Rosenthal syndrome is where OFG occurs with fissured tongue and paralysis of the facial nerve. The cause of the facial paralysis is thought to be caused by the formation of granulomas in the facial nerve, which supplies the muscles of facial expression.

The more common features of the disease are summarized in the acronym POEMS:

Papilledema (swelling of the optic disc) often but not always due to increased intracranial pressure) is the most common ocular sign of POEMS syndrome, occurring in ≥29% of cases. Less frequent ocular findings include cystoid macular edema, serous macular detachment, infiltrative orbitopathy, and venous sinus thrombosis.

Pulmonary disease/ Polyneuropathy: The lungs are often affected at more severe stages of the illness, although since by then physical exertion is usually limited by neuropathy, shortness of breath is unusual. Pulmonary hypertension is the most serious effect on the lungs, and there may also be restriction of chest expansion or impaired gas exchange.

Organomegaly: The liver may be enlarged, and less often the spleen or lymph nodes, though these organs usually function normally.

Edema: Leakage of fluid into the tissues is a common and often severe problem. This may take several forms, including dependent peripheral edema, pulmonary edema, effusions such as pleural effusion or ascites, or generalized capillary leakage (anasarca).

Endocrinopathy: In women, amenorrhea, and in men, gynecomastia, erectile dysfunction and testicular atrophy, are common early symptoms due to dysfunction of the gonadal axis. Other hormonal problems occurring in at least a quarter of patients include type 2 diabetes, hypothyroidism, and adrenal insufficiency.

Monoclonal paraprotein: In most cases a serum myeloma protein can be detected, although this is not universal. This may represent IgG or IgA, but the light chain type is almost always lambda. This is in contrast to most paraproteinemic neuropathies, in which the paraprotein is usually an IgM antibody.

Skin changes: A very wide variety of skin problems have been reported in association with POEMS syndrome. The most common is non-specific hyperpigmentation. The fingernails may be clubbed or white. There may be thickening of the skin, excess hair or hair in unusual places (hypertrichosis), skin angiomas or hemangiomas, or changes reminiscent of scleroderma.

Arthritis mutilans is a rare medical condition involving severe inflammation damaging the joints of the hands and feet, and resulting in deformation and problems with moving the affected areas; it can also affect the spine. As an uncommon arthropathy, arthritis mutilans was originally described as affecting the hands, feet, fingers, and/or toes, but can refer in general to severe derangement of any joint damaged by arthropathy. First described in modern medical literature by Marie and Leri in 1913, in the hands, arthritis mutilans is also known as opera glass hand ("la main en lorgnette" in French), or chronic absorptive arthritis. Sometimes there is foot involvement in which toes shorten and on which painful calluses develop in a condition known as opera glass foot, or "pied en lorgnette".

Villonodular synovitis is a type of synovial swelling.

Types include:

- Pigmented villonodular synovitis (PVNS)

- Giant cell tumor of the tendon sheath (GCTS)

Though they have very different names, they have the same histology, and stain positive for CD68, HAM56, and vimentin.

They are sometimes discussed together.