Undifferentiated connective tissue disease

Last updated

Undifferentiated connective tissue disease
Other nameslatent Lupus, incomplete lupus
Specialty Immunology, rheumatology   OOjs UI icon edit-ltr-progressive.svg
Symptoms dry eyes, dry mouth, hair loss, joint inflammation, joint pain, mouth ulcers, positive ANA test, raynaud's phenomenon, sun-sensitive rash...

Undifferentiated connective tissue disease (UCTD) (also known as latent lupus or incomplete lupus [1] ) is a disease in which the connective tissues are targeted by the immune system. It is a serological and clinical manifestation of an autoimmune disease. When there is proof of an autoimmune disease, but the disease does not correspond to any specific autoimmune disease (such as systemic lupus erythematosus (SLE), scleroderma, [2] mixed connective tissue disease, Sjögren syndrome, systemic sclerosis, polymyositis, dermatomyositis, or rheumatoid arthritis), it will be diagnosed as UCTD. This is also the case of major rheumatic diseases whose early phase was defined by LeRoy et al [3] in 1980 as undifferentiated connective tissue disease.

Contents

The term is sometimes used interchangeably with mixed connective tissue disease (MCTD), as it is an overlap syndrome. However, some researchers believe that MCTD is a clinically distinct entity and is strongly associated with the presence of titer high in antibodies Ribonucleoproteins (RNP). [4]

It is estimated that up to 25% of people with systemic autoimmune disease could be considered to have UCTD. [5]

There are many people who have features of connective tissue disease, such as blood test results and external characteristics, but do not fulfill the diagnostic criteria established for any one disease. These people are considered to have undifferentiated connective tissue disease (UCTD). [6] [3]

Classification

UCTD is not specifically included in the WHOs ICD-11 disease classification system, but may be included in the 'diseases of the immune system' group. [7]

Signs and symptoms

The presentation of the disease varies considerably from one patient to another. [8]

Generally, the symptoms include nonspecific symptoms common to connective tissue diseases such as

These can be the initial presentation for some patients. [3]

Other symptoms associated with UCTD include : [11]

Clinical presentation in some people diagnosed with UCTD may show : [13]

Pulmonary involvement, such as nonspecific interstitial pneumonia, can be a complication of the disease. [5]

Mechanism

UCTD is caused[ citation needed ] by genetic and environmental factors. It may be triggered[ citation needed ] by factors such as:

T-cell hypothesis

Populations of regulatory T cells are believed to be responsible[ citation needed ] for the onset of the disease. When there is a decline of these cells, manifestations of diseases begin to appear, giving an idea of the vital role of these cells in the prevention of autoimmune diseases. Moreover, an additional decrease could unfortunately worsen the pathological state and lead to the differentiation of an undifferentiated connective tissue disease into a differentiated connective tissue disease with a poorer prognosis. Due to the wide range of variation in the inclusion criteria of the disease, up to 50% of patients diagnosed with connective tissue disease may have undifferentiated disease of the underlying connective tissue.

Diagnosis and research inclusion

Diagnosis

There are no formal diagnostic criteria for UCTD. It is determined by a differential diagnosis. Diagnostic tests are undertaken to determine whether a patient has a disease assured or undifferentiated of the connective tissues. [10]

Patients with UCTD usually have positive ANA (antinuclear antibody), and raised ESR (erythrocyte sedimentation rate) values, without typical autoantibody specificities. [14] Some 20% of the general population, [15] and up to 15% of completely healthy people, [16] test positive for ANA, but nonetheless this is regarded by some as almost always a sign of an autoimmune disorder. [12] If more specific types of ANAs or other proteins are present, other autoimmune conditions (not UCTD) are implied. [12] [17]

Other mechanisms that may be used[ citation needed ] are tests for Anti-histone antibodies, Chromatin and vitamin D, and chest X-ray to show signs of pericardial effusion.[ citation needed ]

Classification criteria

Patients may be included for UCTD research if they have:

Treatment

UCTD is normally managed primarily as an outpatient. Meds can be used to manage aspects of the disease. [3]

Treatment depends largely on the progression of the individual disease and the nature of the symptoms presented. Antimalarial medications, corticosteroids and other medications may be prescribed, as the treating physician considers appropriate: [19]

In severe cases, immunosuppressive drugs may be used.

Possible complications

Complications are present with an affected or injured system, such as the lesions and long-term inflammation in the pulmonary system, interstitial lung disease (in 88% of cases, severe interstitial lung disease) or pulmonary fibrosis. If the heart is affected, hypertrophy can occur, leading to cardiomegaly. [3] Organs can also be affected (neurological or renal manifestations) and life-threatening conditions can occur.

Affected pregnant women follow careful clinical observation because they are more likely to see disease progression. Those with the disease at the beginning of pregnancy will keep the disease undifferentiated against 25% who progress to a defined disease at the end of pregnancy. In addition, 45% of pregnancies with the disease end in preterm birth.

Prevention and patient education

Early recognition and knowledge of the onset of UCTD can help patients manage and control their disease. Patients should be informed of common agents and triggers to help manage symptoms to shorten the duration of the disease and prevent complications.[ citation needed ]

Improving health care team outcomes

Undifferentiated connective tissue disease occurs for various reasons; underlying factors may affect several organs depending on individual sensitivity. Coordination of care between primary clinicians and experts (like rheumatologists) can help achieve optimal patient outcomes.[ citation needed ]

Outlook

Progression

30–40% of UCTD cases may develop into a defined connective tissue disease as more diagnostic criteria are progressively met. [3] This generally happens within five years of onset. [20]

Several factors may help predict progression:

The rate of progression is higher in the first five years following the onset of the disease and tends to decrease over time. Patients progressing to a defined disease seem to see a slight progression of the disease with a mitigated risk of developing complications. [3]

Remaining undifferentiated

Most UCTD cases will remain undifferentiated. UCTD itself usually has a mild clinical course, particularly if there is low organ involvement. Most patients who remain undifferentiated tend to not experience major organ involvement. [23]

Up to 10–20% of patients diagnosed with UCTD will never progress to a defined disease and their symptoms will decrease or disappear. [3]

About 12% of patients will go into remission. [24] [23]

Particular studies

Epidemiology

Up to 90% of UCTD cases are females between 32 and 44 years old. [3] [27] In the United States up to 78% of patients were female, against 93 to 95% in Italy and 94% in Hungary. Higher female prevalence is common in autoimmune diseases.[ citation needed ]

In the United States, up to 72% of patients diagnosed with UCTD had white skin. [3]

Prevalence of UCTD has been estimated at 2 people per 100,000 people per year. [28] Annual incidence has been estimated as varying from 41 to 149 per 100,000 adults. [29] [30] [31] It has also been suggested that UCTD is a relatively common condition seen in rheumatology practice, making up 10–20% of referrals to tertiary care clinics. [32]

Classical epidemiological data for UCTD are not available due to the limited literature exploring the disease. Also, differences in patient selection criteria in existing studies make comparisons between them difficult. [1]

History

The term was first suggested in 1980, [33] as connective tissue disease in patients whose features did not meet other classification criteria. [3] In 1999 a study noted, "In recent years there has been growing concern regarding the diagnosis of incomplete forms of the autoimmune diseases" [26] and the first classification criteria were proposed in that year. [1]

Historically the condition was sometimes called undifferentiated connective tissue syndrome, latent lupus or incomplete lupus. [1]

Related Research Articles

<span class="mw-page-title-main">Sjögren syndrome</span> Autoimmune disease affecting the bodys moisture-producing glands

Sjögren's disease (SjD) is a long-term autoimmune disease that primarily affects the body's exocrine glands, particularly the lacrimal and salivary glands. Common symptoms include dry mouth, dry eyes and often seriously affect other organ systems, such as the lungs, kidneys, and nervous system.

<span class="mw-page-title-main">Antiphospholipid syndrome</span> Immune disorder leading to increased risk of blood clots

Antiphospholipid syndrome, or antiphospholipid antibody syndrome, is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS can lead to blood clots (thrombosis) in both arteries and veins, pregnancy-related complications, and other symptoms like low platelets, kidney disease, heart disease, and rash. Although the exact etiology of APS is still not clear, genetics is believed to play a key role in the development of the disease.

<span class="mw-page-title-main">Antinuclear antibody</span> Autoantibody that binds to contents of the cell nucleus

Antinuclear antibodies are autoantibodies that bind to contents of the cell nucleus. In normal individuals, the immune system produces antibodies to foreign proteins (antigens) but not to human proteins (autoantigens). In some cases, antibodies to human antigens are produced; these are known as autoantibodies.

Rheumatoid factor (RF) is the autoantibody that was first found in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG and different RFs can recognize different parts of the IgG-Fc. RF and IgG join to form immune complexes that contribute to the disease process such as chronic inflammation and joint destruction at the synovium and cartilage.

<span class="mw-page-title-main">CREST syndrome</span> Connective tissue disorder

CREST syndrome, also known as the limited cutaneous form of systemic sclerosis (lcSSc), is a multisystem connective tissue disorder. The acronym "CREST" refers to the five main features: calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia.

An autoantibody is an antibody produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases are associated with such antibodies.

Connective tissue disease, also known as connective tissue disorder, or collagen vascular diseases, refers to any disorder that affects the connective tissue. The body's structures are held together by connective tissues, consisting of two distinct proteins: elastin and collagen. Tendons, ligaments, skin, cartilage, bone, and blood vessels are all made of collagen. Skin and ligaments contain elastin. The proteins and the body's surrounding tissues may suffer damage when these connective tissues become inflamed.

Extractable nuclear antigens (ENAs) are over 100 different soluble cytoplasmic and nuclear antigens. They are known as "extractable" because they can be removed from cell nuclei using saline and represent six main proteins: Ro, La, Sm, RNP, Scl-70, Jo1. Most ENAs are part of spliceosomes or nucleosomes complexes and are a type of small nuclear ribonucleoprotein (snRNPS). The location in the nucleus and association with spliceosomes or nucleosomes results in these ENAs being associated with additional RNA and proteins such as polymerases. This quality of ENAs often makes it difficult to purify and quantify their presence for clinical use.

Catastrophic antiphospholipid syndrome (CAPS), also known as Asherson's syndrome, is a rare autoimmune disease in which widespread, intravascular clotting causes multi-organ failure. The syndrome is caused by antiphospholipid antibodies that target a group of proteins in the body that are associated with phospholipids. These antibodies activate endothelial cells, platelets, and immune cells, ultimately causing a large inflammatory immune response and widespread clotting. CAPS was first described by Ronald Asherson in 1992. The syndrome exhibits thrombotic microangiopathy, multiple organ thromboses, and in some cases tissue necrosis and is considered an extreme or catastrophic variant of the antiphospholipid syndrome.

Mixed connective tissue disease (MCTD) is a systemic autoimmune disease that shares characteristics with at least two other systemic autoimmune diseases, including systemic sclerosis (Ssc), systemic lupus erythematosus (SLE), polymyositis/dermatomyositis (PM/DM), and rheumatoid arthritis. 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.

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

Childhood arthritis is an umbrella term used to describe any rheumatic disease or chronic arthritis-related condition which affects individuals under the age of 16. There are several subtypes that differentiate themselves via prognosis, complications, and treatments. Most types are autoimmune disorders, where an individual's immune system may attack its own healthy tissues and cells.

Scleromyositis, is an autoimmune disease. People with scleromyositis have symptoms of both systemic scleroderma and either polymyositis or dermatomyositis, and is therefore considered an overlap syndrome. Although it is a rare disease, it is one of the more common overlap syndromes seen in scleroderma patients, together with MCTD and Antisynthetase syndrome. Autoantibodies often found in these patients are the anti-PM/Scl (anti-exosome) antibodies.

An overlap syndrome is a medical condition which shares features of at least two more widely recognised disorders. Examples of overlap syndromes can be found in many medical specialties such as overlapping connective tissue disorders in rheumatology, and overlapping genetic disorders in cardiology.

<span class="mw-page-title-main">Anti-centromere antibodies</span> Type of autoantibody

Anti-centromere antibodies are autoantibodies specific to centromere and kinetochore function. They occur in some autoimmune diseases, frequently in limited systemic scleroderma, and occasionally in the diffuse form of scleroderma. They are rare in other rheumatic diseases and in healthy persons.

Anti-topoisomerase antibodies (ATA) are autoantibodies directed against topoisomerase and found in several diseases, most importantly scleroderma. Diseases with ATA are autoimmune disease because they react with self-proteins. They are also referred to as anti-DNA topoisomerase I antibody.

<span class="mw-page-title-main">Autoimmune disease</span> Disorders of adaptive immune system

An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated that there are more than 80 recognized autoimmune diseases, with recent scientific evidence suggesting the existence of potentially more than 100 distinct conditions. Nearly any body part can be involved.

<span class="mw-page-title-main">Anti-dsDNA antibodies</span> Group of anti-nuclear antibodies

Anti-double stranded DNA (Anti-dsDNA) antibodies are a group of anti-nuclear antibodies (ANA) the target antigen of which is double stranded DNA. Blood tests such as enzyme-linked immunosorbent assay (ELISA) and immunofluorescence are routinely performed to detect anti-dsDNA antibodies in diagnostic laboratories. They are highly diagnostic of systemic lupus erythematosus (SLE) and are implicated in the pathogenesis of lupus nephritis.

<span class="mw-page-title-main">Lupus</span> Autoimmune disease in which the immune system attacks healthy tissue

Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common symptoms include painful and swollen joints, fever, chest pain, hair loss, mouth ulcers, swollen lymph nodes, feeling tired, and a red rash which is most commonly on the face. Often there are periods of illness, called flares, and periods of remission during which there are few symptoms.

<span class="mw-page-title-main">Anti-SSA/Ro autoantibodies</span> Type of anti-nuclear autoantibodies

Anti-SSA autoantibodies are a type of anti-nuclear autoantibodies that are associated with many autoimmune diseases, such as systemic lupus erythematosus (SLE), SS/SLE overlap syndrome, subacute cutaneous lupus erythematosus (SCLE), neonatal lupus and primary biliary cirrhosis. They are often present in Sjögren's syndrome (SS). Additionally, Anti-Ro/SSA can be found in other autoimmune diseases such as systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), rheumatoid arthritis (RA), and mixed connective tissue disease (MCTD), and are also associated with heart arrhythmia.

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

Antisynthetase syndrome (ASS) is a multisystematic autoimmune disease associated with inflammatory myositis, interstitial lung disease, and antibodies directed against various synthetases of aminoacyl-transfer RNA. Other common symptoms include mechanic's hands, Raynaud's phenomenon, arthritis, and fever.

References

  1. 1 2 3 4 Mosca M, Neri R, Bombardieri S (1999). "Undifferentiated connective tissue diseases (UCTD): a review of the literature and a proposal for preliminary classification criteria" (PDF). Clinical and Experimental Rheumatology. 17 (5): 615–620. PMID   10544849.
  2. ↑ Bodolay E, Szegedi G (May 2009). "[Undifferentiated connective tissue disease]". Orvosi Hetilap (in Hungarian). 150 (19): 867–872. doi:10.1556/OH.2009.28610. PMID   19403430. S2CID   39614044.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 Marwa K, Anjum F (2024). "Undifferentiated Connective Tissue Disease". StatPearls. StatPearls Publishing. PMID   34283427.
  4. ↑ Hoffman RW, Greidinger EL (2002). "Chapter 23: Mixed connective tissue disease". In George C. Tsokos (ed.). Modern Therapeutics in Rheumatic Diseases. Humana Press. pp. 347–357. doi:10.1007/978-1-59259-239-5_23 (inactive 1 November 2024). ISBN   978-1-59259-239-5.{{cite book}}: CS1 maint: DOI inactive as of November 2024 (link)
  5. 1 2 Lunardi F, Balestro E, Nordio B, Cozzi F, Polverosi R, Sfriso P, et al. (June 2011). "Undifferentiated connective tissue disease presenting with prevalent interstitial lung disease: case report and review of literature". Diagnostic Pathology. 6 (50): 50. doi: 10.1186/1746-1596-6-50 . PMC   3126759 . PMID   21645423.
  6. ↑ "Undifferentiated connective tissue disease (UCTD)". Clinton Township, MI: Autoimmune Association.
  7. ↑ "ICD-11 for Mortality and Morbidity Statistics".
  8. ↑ Owlia MB (2006). "Clinical spectrum of connective tissue disorders" (PDF). Journal, Indian Academy of Clinical Medicine. 7 (3): 218.
  9. ↑ Zielinski MR, Systrom DM, Rose NR (2019). "Fatigue, Sleep, and Autoimmune and Related Disorders". Frontiers in Immunology. 10: 1827. doi: 10.3389/fimmu.2019.01827 . PMC   6691096 . PMID   31447842.
  10. 1 2 Doria A, Mosca M, Gambari PF, Bombardieri S (February 2005). "Defining unclassifiable connective tissue diseases: incomplete, undifferentiated, or both?" (PDF). The Journal of Rheumatology. 32 (2): 213–215. PMID   15693073.
  11. ↑ Vaz CC, Couto M, Medeiros D, Miranda L, Costa J, Nero P, et al. (August 2009). "Undifferentiated connective tissue disease: a seven-center cross-sectional study of 184 patients". Clinical Rheumatology. 28 (8): 915–921. doi:10.1007/s10067-009-1175-2. hdl: 10400.4/500 . PMID   19390908. S2CID   3133285.
  12. 1 2 3 4 Rodgers L (September 27, 2020). "What Is Undifferentiated Connective Tissue Disease? Here's How to Know If You Have It".
  13. ↑ Berman JR (2017). "Undifferentiated Connective Tissue Disease - In-Depth Overview". Hospital for Special Surgery.
  14. 1 2 Talotta R (2023). "The diagnostic laboratory tests in rheumatic diseases". Translational Autoimmunity. pp. 113–148. doi:10.1016/B978-0-323-85831-1.00007-3. ISBN   978-0-323-85831-1.
  15. ↑ Zanussi JT, Zhao J, Wei WQ, Karakoc G, Chung CP, Feng Q, et al. (August 2023). "Clinical diagnoses associated with a positive antinuclear antibody test in patients with and without autoimmune disease". BMC Rheumatology. 7 (1): 24. doi: 10.1186/s41927-023-00349-4 . PMC   10405518 . PMID   37550754.
  16. ↑ "Antinuclear Antibodies (ANA)". rheumatology.org.
  17. ↑ "For example: People with lupus may also test positive for anti-double-stranded DNA antibody (anti-dsDNA) and anti-Smith (anti-Sm) antibody. People with myositis may have elevated levels of a muscle enzyme called creatine kinase (CK) that could be a sign of polymyositis. People with rheumatoid arthritis may test positive for the antibodies anti-cyclic citrullinated peptides (anti-CCP) and rheumatoid factor. People with Sjögren’s may test positive for anti-Ro (SS-A) and anti-La (SS-B) antibodies as well as rheumatoid factor."
  18. ↑ "Undifferentiated Connective Tissue Disease – In-Depth". Hospital for Special Surgery (HSS).
  19. 1 2 Mosca M, Baldini C, Bombardieri S (2004). "Undifferentiated connective tissue diseases in 2004" (PDF). Clinical and Experimental Rheumatology. 22 (3 Suppl 33): S14–S18. PMID   15344591.
  20. ↑ Herrick A, Hughes M (2013). "Overlap/Undifferentiated syndromes". Oxford Textbook of Rheumatology. pp. 1069–1078. doi:10.1093/med/9780199642489.003.0129_update_001. ISBN   978-0-19-964248-9.
  21. ↑ Dyball S, Rodziewicz M, Mendoza-Pinto C, Bruce IN, Parker B (November 2022). "Predicting progression from undifferentiated connective tissue disease to definite connective tissue disease: A systematic review and meta-analysis". Autoimmunity Reviews. 21 (11): 103184. doi: 10.1016/j.autrev.2022.103184 . PMID   36031048.
  22. ↑ Zold E, Szodoray P, Gaal J, Kappelmayer J, Csathy L, Gyimesi E, et al. (2008). "Vitamin D deficiency in undifferentiated connective tissue disease". Arthritis Research & Therapy. 10 (5): R123. doi: 10.1186/ar2533 . PMC   2592813 . PMID   18928561.
  23. 1 2 3 4 Pepmueller PH (January 23, 2016). "Undifferentiated Connective Tissue Disease, Mixed Connective Tissue Disease, and Overlap Syndromes in Rheumatology". Missouri Medicine. 113 (2): 136–140. PMC   6139943 . PMID   27311225.
  24. ↑ Bodolay E, Csiki Z, Szekanecz Z, Ben T, Kiss E, Zeher M, et al. (2003). "Five-year follow-up of 665 Hungarian patients with undifferentiated connective tissue disease (UCTD)". Clinical and Experimental Rheumatology. 21 (3): 313–320. PMID   12846049.
  25. ↑ García-González M, Rodríguez-Lozano B, Bustabad S, Ferraz-Amaro I (2017). "Undifferentiated connective tissue disease: predictors of evolution into definite disease". Clinical and Experimental Rheumatology. 35 (5): 739–745. PMID   28770704.
  26. 1 2 Danieli MG, Fraticelli P, Franceschini F, Cattaneo R, Farsi A, Passaleva A, et al. (1999). "Five-year follow-up of 165 Italian patients with undifferentiated connective tissue diseases". Clinical and Experimental Rheumatology. 17 (5): 585–591. PMID   10544842.
  27. ↑ Angum F, Khan T, Kaler J, Siddiqui L, Hussain A (May 2020). "The Prevalence of Autoimmune Disorders in Women: A Narrative Review". Cureus. 12 (5): e8094. doi: 10.7759/cureus.8094 . PMC   7292717 . PMID   32542149.
  28. ↑ Purohit R, Shahu Khal R, Gokalp G, Sambandan R, Bhanusali N (June 2023). "Undifferentiated Connective Tissue Disease With Isolated Diaphragmatic Dysfunction". Cureus. 15 (6): e40515. doi: 10.7759/cureus.40515 . PMC   10350301 . PMID   37461764.
  29. ↑ Deane KD, El-Gabalawy H (April 2014). "Pathogenesis and prevention of rheumatic disease: focus on preclinical RA and SLE". Nature Reviews. Rheumatology. 10 (4): 212–228. doi:10.1038/nrrheum.2014.6. PMC   4090326 . PMID   24514912.
  30. ↑ Spinillo A, Beneventi F, Caporali R, Ramoni V, Montecucco C (December 2017). "Undifferentiated connective tissue diseases and adverse pregnancy outcomes. An undervalued association?". American Journal of Reproductive Immunology. 78 (6). doi:10.1111/aji.12762. PMID   28921728. S2CID   13081256.
  31. ↑ Serena C, Clemenza S, Simeone S, Zullino S, Ottanelli S, Rambaldi MP, et al. (January 23, 2022). "Undifferentiated Connective Tissue Disease in Pregnancy: A Topic Yet to be Explored". Frontiers in Pharmacology. 13: 820760. doi: 10.3389/fphar.2022.820760 . PMC   8811283 . PMID   35126164.
  32. ↑ Olsen NJ (2019). "Incomplete Lupus, Undifferentiated Connective Tissue Disease, and Mixed Connective Tissue Disease". Dubois' Lupus Erythematosus and Related Syndromes. pp. 606–613. doi:10.1016/B978-0-323-47927-1.00048-7. ISBN   978-0-323-47927-1.
  33. ↑ LeRoy EC, Maricq HR, Kahaleh MB (March 1980). "Undifferentiated connective tissue syndromes". Arthritis and Rheumatism. 23 (3): 341–343. doi:10.1002/art.1780230312. PMID   7362686.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.