Rheumatoid nodule

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Rheumatoid nodule
Histopathology of a rheumatoid nodule.png
Micrograph of a rheumatoid nodule, showing the characteristic palisading granuloma with a core consisting of necrotic collagen and fibrin. H&E stain.
Specialty Rheumatology

A rheumatoid nodule is a lump of tissue, or an area of swelling, that appears on the exterior of the skin usually around the olecranon (tip of the elbow) or the interphalangeal joints (finger knuckles), but can appear in other areas. [1] There are four different types of rheumatoid nodules: subcutaneous rheumatoid nodules, cardiac nodules, pulmonary nodules, and central nervous systems nodules. These nodules occur almost exclusively in association with rheumatoid arthritis. Very rarely do rheumatoid nodules occur as rheumatoid nodulosis (multiple nodules on the hands or other areas) in the absence of rheumatoid arthritis. Rheumatoid nodules can also appear in areas of the body other than the skin. Less commonly they occur in the lining of the lungs or other internal organs. The occurrence of nodules in the lungs of miners exposed to silica dust was known as Caplan’s syndrome. [2] Rarely, the nodules occur at diverse sites on body (e.g., upper eyelid, distal region of the soles of the feet, vulva, and internally in the gallbladder, lung, heart valves, larynx, and spine). [3]

Contents

Rheumatoid nodules can vary in size from 2 mm to 5 cm and are usually rather firm to the touch. Quite often they are associated with synovial pockets or bursae. About 5% of people with rheumatoid arthritis have such nodules within two years of disease onset, and the cumulative prevalence is about 20–30%. [4] Risk factors of developing rheumatoid nodules include as smoking and trauma to small vessels. [5]

In the majority of the time, nodules are not painful or disabling in any way. They are usually more of an unsightly nuisance. However, rheumatoid nodules can become painful when infection or ulcers occur on the skin of the nodule. Some nodules may disappear over time, but other may grow larger, making nodular size difficult to predict. [6]

Treatment of rheumatoid nodules can be quite difficult, but both surgical removal and injection of corticosteroids have shown good results.

Pathophysiology

Although the exact process is unknown, there are a few hypotheses for the generation of rheumatoid nodules. It has been observed that rheumatoid nodules frequently form over extensor sites and areas vulnerable to trauma. [7] The trauma causes inflammatory particles to build up and leads to a secondary inflammatory response which ultimately causes fibrin release and necrosis. [5] Another hypothesis suggests that the inflammation of blood vessels activates complement components, which leads to the deposit of rheumatoid factors and fibrin. [5]

The rheumatoid nodule is the most common cutaneous manifestation of rheumatoid arthritis. [7] Rheumatoid arthritis involves chronic inflammation of synovial membranes, which leads to degradation of articular cartilage and the juxta-articular bone. Inflammation is caused by T cells, B cells, and monocytes when endothelial cells are activated. Neovascularization, the growth of new blood vessels, serves as an additional marker for rheumatoid arthritis. A hyperplastic synovial lining layer can be caused by the expansion of synovial fibroblast and macrophage cells. [7] This expansion of the synovial membrane, sometimes referred to as "pannus", can lead to bony erosions and cartilage degradation at the site of the cartilage-bone junction in the periarticular bone. [8]

The cause of rheumatoid arthritis is unknown. It is speculated that both genetic and environmental factors contribute to the development of rheumatoid arthritis. Gene loci and antigens, such as HLA class II antigens, have been seen as closely associated with rheumatoid arthritis. [9] Environmental risk factors include smoking, periodontitis, viral infections, and gut, mouth, and lung microbiomes. Researchers have noted that Prevotella species, which are expanded in the gastrointestinal tract in early RA, and Porphyromonas gingivalis, which is associated with periodontitis, may have a role in pathogenesis. [10]

Pathology

Histological examination of nodules shows that they consist of a shell of fibrous tissue surrounding a center of fibrinoid necrosis. [11] Pea-sized nodules have one center. Larger nodules tend to be multilocular, with many separate shells or with connections between the necrotic centers. Individual necrotic centers may contain a cleft or several centers of necrosis may all open on to a large bursal pocket containing synovial fluid.

The boundary between the necrotic center and the outer fibrous shell is made up of the characteristic feature of the nodule, which is known as a cellular palisade. The palisade is a densely packed layer of macrophages and fibroblasts which tend to be arranged radially, like the seeds of a kiwifruit or fig. [11] Further out into the fibrous shell there is a zone that contains T cells and plasma cells in association with blood vessels. [12] The histology of pulmonary nodules are similar to that of subcutaneous nodules, with central necrosis surrounded by palisading macrophages and inflammatory infiltrate. [5]

Risk factors

Rheumatoid nodules develop if a person currently has rheumatoid arthritis. However, not all people with rheumatoid arthritis develop rheumatoid nodules. Some risk factors for rheumatoid nodules for people with rheumatoid arthritis may include: [5]

Diagnosis

Differential diagnosis of rheumatoid nodules can be classified from localization, depth pathology, age of onset, persistence, rheumatoid factor, concomitant joint disease, and bone erosions. Diagnosis is typically determined clinically by a rheumatologist. [5] Rheumatoid arthritis associated rheumatoid nodules are typically subcutaneous and occur at extensor sites. The onset typically starts in adulthood and presents with rheumatoid factors and bone erosions, and concomitant joint diseases. The pathology is characterized by central necrosis, palisading mononuclear cells, and perivascular lymphocytic infiltrations. [12]

Rheumatoid nodulosis is characterized by multiple subcutaneous nodules presenting with rheumatoid factors but an absence of joint complaints. The nodules are typically small and concentrated on the extensor sites of the hands and feet, sometimes accompanied by bone erosions. The onset typically starts in adulthood with a pathology similar to rheumatoid arthritis associated rheumatoid nodules. [12]

Benign rheumatoid nodules are often not associated with rheumatoid factors or concomitant joint diseases. [14] They are typically found on the feet, scalp, and pretibial regions. Frequently seen in children before the age of 18, the pathology is similar to that of rheumatoid arthritis associated rheumatoid nodules. The nodules are non-tender and undergo rapid growth, but also resolve spontaneously. [12] A similar presentation occurring more intracutaneously (superficial) is known as granuloma annulare. [12]

Rheumatic fever nodules are typically associated with acute rheumatic fever in children. They are not accompanied by rheumatoid factors or bone erosions, but are associated with concomitant joint diseases. No larger than the size of peas, they are typically found at extensor sites and processus spinosi of the vertebrae. The pathology is characterized by central necrosis and little histiocytic/lymphocytic infiltration. [12] [15]

Prevalence

There are four different types of rheumatoid nodules: subcutaneous rheumatoid nodules, cardiac nodules, pulmonary nodules and central nervous system nodules.

Subcutaneous rheumatoid nodules

According to a study done by the BARFOT study group, 7% of individuals diagnosed with rheumatoid arthritis reported the presence of subcutaneous rheumatoid nodules upon initial diagnosis. And about 30–40% of all those diagnosed with rheumatoid arthritis reported developing these nodules throughout the course of the disease. [16] Subcutaneous rheumatoid nodules is correlated with the increased risk of cardiovascular and respiratory disease, and those with detected subcutaneous rheumatoid nodules should be assessed for cardiovascular and respiratory risk factors. [1]

Cardiac nodules

Rheumatoid nodules may also form in the heart. Specifically, it could develop in the myocardium, pericardium, and other valvular structures, and these nodules can be discovered through echocardiograms. [17] There are little studies with minimal data on the development of cardiac nodules in association with rheumatoid arthritis, but the general consensus is that such occurrences is relatively rare.

Pulmonary Nodules

The reported prevalence of pulmonary nodules has varying depending on the method of detection. In a 1984 study done on lung biopsies in rheumatoid arthritis, the reported prevalence was about 32% in a sample size of 40 individuals. [18] However, another clinical study utilizing a different method of detection; plain film radiographs of the chest; showed that only 2 out of 516 people (~0.4%) diagnosed with rheumatoid arthritis developed pulmonary nodules. [19] Additionally, other clinical studies have reported increased pulmonary nodule growth following treatments with methotrexate, [13] leflunomide, [20] and etanercept. [21]

Central nervous system nodules

Like cardiac nodules, nodules developing in the central nervous system is also relatively rare. Most reports of nodule growth on the central nervous system also presented with severe stages of erosive joint diseases. [22] Generally, these nodules can be detected through MRI and confirmed through biopsies. As of right now, there are no known mediations that have been reported in reducing nodules in the central nervous systems.

Prevention

There are no methods as of right now to completely prevent the development of rheumatoid nodules, but for those diagnosed with rheumatoid arthritis, proper management of the disease could reduce the risk of nodule formation. Additionally, proper medication adherence, smoking cessation, increasing physical activity, and keeping up with doctor appointments are just some lifestyle changes that could "prevent" nodules. [6]

Treatment

Treatment for rheumatoid nodules may be tricky as some treatments for rheumatoid arthritis can act against the nodules. Common drug therapies for rheumatoid arthritis may show no benefits towards the treatment for rheumatoid nodules. Common drug therapies, such as anti TNF treatment or other immunosuppressive drugs, for rheumatoid arthritis has shown little effect on the nodules. [23] In fact, it has been shown that Methotrexate, a drug often used in rheumatoid arthritis, is actually correlated with the increased risk of nodule formation. [13] Because rheumatoid nodules also cause pain or nerve entrapment, treatment for these symptoms with nonsteroidal anti-inflammatory drugs may be sufficient. [5] Other drug therapies, such as corticosteroids, have shown to decrease nodular size, however, it can increase the risk of infection as well. [24] Local corticosteroid injections seems to be the most studied treatment for rheumatoid nodules as of now.

Surgery to have the nodule removed is another option that can be done to treat rheumatoid nodules. However, usually these are usually only indicated in the case of eroding/ necrotising skin. [25]

See also

Related Research Articles

<span class="mw-page-title-main">Arthritis</span> Type of joint disorder

Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In some types of arthritis, other organs are also affected. Onset can be gradual or sudden.

<span class="mw-page-title-main">Rheumatoid arthritis</span> Type of autoimmune arthritis

Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involved, with the same joints typically involved on both sides of the body. The disease may also affect other parts of the body, including skin, eyes, lungs, heart, nerves, and blood. This may result in a low red blood cell count, inflammation around the lungs, and inflammation around the heart. Fever and low energy may also be present. Often, symptoms come on gradually over weeks to months.

<span class="mw-page-title-main">Methotrexate</span> Chemotherapy and immunosuppressant medication

Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leukemia, lung cancer, lymphoma, gestational trophoblastic disease, and osteosarcoma. Types of autoimmune diseases it is used for include psoriasis, rheumatoid arthritis, and Crohn's disease. It can be given by mouth or by injection.

<span class="mw-page-title-main">Sarcoidosis</span> Medical condition

Sarcoidosis is a disease involving abnormal collections of inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph nodes. Less commonly affected are the eyes, liver, heart, and brain, though any organ can be affected. The signs and symptoms depend on the organ involved. Often, no, or only mild, symptoms are seen. When it affects the lungs, wheezing, coughing, shortness of breath, or chest pain may occur. Some may have Löfgren syndrome with fever, large lymph nodes, arthritis, and a rash known as erythema nodosum.

<span class="mw-page-title-main">Disease-modifying antirheumatic drug</span> Category of drugs

Disease-modifying antirheumatic drugs (DMARDs) comprise a category of otherwise unrelated disease-modifying drugs defined by their use in rheumatoid arthritis to slow down disease progression. The term is often used in contrast to nonsteroidal anti-inflammatory drugs and steroids.

<span class="mw-page-title-main">Septic arthritis</span> Medical condition

Acute septic arthritis, infectious arthritis, suppurative arthritis, pyogenic arthritis, osteomyelitis, or joint infection is the invasion of a joint by an infectious agent resulting in joint inflammation. Generally speaking, symptoms typically include redness, heat and pain in a single joint associated with a decreased ability to move the joint. Onset is usually rapid. Other symptoms may include fever, weakness and headache. Occasionally, more than one joint may be involved, especially in neonates, younger children and immunocompromised individuals. In neonates, infants during the first year of life, and toddlers, the signs and symptoms of septic arthritis can be deceptive and mimic other infectious and non-infectious disorders.

<span class="mw-page-title-main">Psoriatic arthritis</span> Long-term inflammatory arthritis

Psoriatic arthritis (PsA) is a long-term inflammatory arthritis that occurs in people affected by the autoimmune disease psoriasis. The classic feature of psoriatic arthritis is swelling of entire fingers and toes with a sausage-like appearance. This often happens in association with changes to the nails such as small depressions in the nail (pitting), thickening of the nails, and detachment of the nail from the nailbed. Skin changes consistent with psoriasis frequently occur before the onset of psoriatic arthritis but psoriatic arthritis can precede the rash in 15% of affected individuals. It is classified as a type of seronegative spondyloarthropathy.

<span class="mw-page-title-main">Granulomatosis with polyangiitis</span> Medical condition

Granulomatosis with polyangiitis (GPA), previously known as Wegener's granulomatosis (WG), after the German physician Friedrich Wegener, is a rare long-term systemic disorder that involves the formation of granulomas and inflammation of blood vessels (vasculitis). It is an autoimmune disease and a form of vasculitis that affects small- and medium-size vessels in many organs but most commonly affects the upper respiratory tract, lungs and kidneys. The signs and symptoms of GPA are highly varied and reflect which organs are supplied by the affected blood vessels. Typical signs and symptoms include nosebleeds, stuffy nose and crustiness of nasal secretions, and inflammation of the uveal layer of the eye. Damage to the heart, lungs and kidneys can be fatal.

Mixed connective tissue disease, commonly abbreviated as MCTD, is an autoimmune disease characterized by the presence of elevated blood levels of a specific autoantibody, now called anti-U1 ribonucleoprotein (RNP), together with a mix of symptoms of systemic lupus erythematosus (SLE), scleroderma, and polymyositis. The idea behind the "mixed" disease is that this specific autoantibody is also present in other autoimmune diseases such as systemic lupus erythematosus, polymyositis, scleroderma, etc. MCTD was characterized as an individual disease in 1972 by Sharp et al., and the term was introduced by Leroy in 1980.

A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma, so TNF inhibitors may be used in their treatment. The important side effects of TNF inhibitors include lymphomas, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects.

Caplan's syndrome is a combination of rheumatoid arthritis (RA) and pneumoconiosis that manifests as intrapulmonary nodules, which appear homogeneous and well-defined on chest X-ray.

Lymphomatoid granulomatosis (LYG or LG) is a very rare lymphoproliferative disorder first characterized in 1972. Lymphomatoid means lymphoma-like and granulomatosis denotes the microscopic characteristic of the presence of granulomas with polymorphic lymphoid infiltrates and focal necrosis within it.

Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis, cytokine release syndrome, COVID‑19, and systemic sclerosis-associated interstitial lung disease (SSc-ILD). It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer. Tocilizumab was jointly developed by Osaka University and Chugai, and was licensed in 2003 by Hoffmann-La Roche.

Synovectomy is a procedure where the synovial tissue surrounding a joint is removed. This procedure is typically recommended to provide relief from a condition in which the synovial membrane or the joint lining becomes inflamed and irritated and is not controlled by medication alone. If arthritis is not controlled, it can lead to irreversible joint damage. The synovial membrane or "synovium" encloses each joint and also secretes a lubricating fluid that allows different joint motions such as rolling, folding and stretching. When the synovium becomes inflamed or irritated, it increases fluid production, resulting in warmth, tenderness, and swelling in and around the joint.

Rheumatoid vasculitis is skin condition that is a typical feature of rheumatoid arthritis, presenting as peripheral vascular lesions that are localized purpura, cutaneous ulceration, and gangrene of the distal parts of the extremities.

Rheumatoid nodulosis is a cutaneous condition associated with rheumatoid arthritis, characterized by the appearance of multiple nodules, most often on the hands.

Rheumatoid lung disease is a disease of the lung associated with RA, rheumatoid arthritis. Rheumatoid lung disease is characterized by pleural effusion, pulmonary fibrosis, lung nodules and pulmonary hypertension. Common symptoms associated with the disease include shortness of breath, cough, chest pain and fever. It is estimated that about one quarter of people with rheumatoid arthritis develop this disease, which are more likely to develop among elderly men with a history of smoking.

Olokizumab (OKZ) sold under the name Artlegia, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis and COVID-19. It is a humanized monoclonal antibody against the interleukin-6 (IL-6). IL-6 is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases. Olokizumab is the first interleukin-6 (IL-6) inhibitor approved for treatment of rheumatoid arthritis which blocks directly cytokine instead of its receptor. Olokizumab specifically binds to IL-6 at Site 3, blocking IL-6 ability to form hexameric complex. Olokizumab was developed by R-Pharm group, and was launched in 2020.

Diagnostic delay is the time interval between the onset of symptoms and confirmed diagnosis of a disease. For a variety of reasons, including the mitigation of disease severity and financial expense, it is desirable for this delay to be minimized.

<span class="mw-page-title-main">Antiarthritics</span> Drug class

An antiarthritic is any drug used to relieve or prevent arthritic symptoms, such as joint pain or joint stiffness. Depending on the antiarthritic drug class, it is used for managing pain, reducing inflammation or acting as an immunosuppressant. These drugs are typically given orally, topically or through administration by injection. The choice of antiarthritic medication is often determined by the nature of arthritis, the severity of symptoms as well as other factors, such as the tolerability of side effects.

References

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  18. ↑ Koslow M, Young JR, Baqir M, Joanne EY, Johnson G, Ryu J (October 2017). "Clinical and Imaging Features Distinguish Rheumatoid Pulmonary Nodules From Malignancy in Rheumatoid Patients". Chest. 152 (4): A752. doi:10.1016/j.chest.2017.08.782.
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