|Other names||Sjögren's syndrome, sicca syndrome|
|Image with a microscope of focal lymphoid infiltration in the minor salivary gland associated with Sjögren syndrome.|
|Symptoms||Dry mouth, dry eyes, other areas of dryness|
|Usual onset||Middle age|
|Causes||Autoimmune disease (unknown cause)|
|Diagnostic method||Tissue biopsy, blood tests|
|Differential diagnosis||Medication side effect, anxiety, sarcoidosis, amyloidosis|
|Treatment||Artificial tears, medications to reduce inflammation, surgery|
|Prognosis||Normal life expectancy|
Sjögren syndrome (SjS, SS) is a long-term autoimmune disease that affects the body's moisture-producing glands. Primary symptoms are a dry mouth and dry eyes. Other symptoms can include dry skin, vaginal dryness, a chronic cough, numbness in the arms and legs, feeling tired, muscle and joint pains, and thyroid problems. Those affected are at an increased risk (5%) of lymphoma.
While the exact cause is unclear, it is believed to involve a combination of genetics and an environmental trigger such as exposure to a virus or bacteria. It can occur independently of other health problems (primary Sjögren syndrome) or as a result of another connective tissue disorder (secondary Sjögren syndrome). The inflammation that results progressively damages the glands. Diagnosis is by biopsy of moisture-producing glands and blood tests looking for specific antibodies. On biopsy there are typically lymphocytes within the glands.
Treatment is directed at the person's symptoms. For dry eyes artificial tears, medications to reduce inflammation, punctal plugs, or surgery to shut the tear ducts, may be tried. For a dry mouth, chewing gum (preferably sugar free), sipping water, or a saliva substitute may be used. In those with joint or muscle pain, ibuprofen may be used. Medications that can cause dryness, such as antihistamines, may also be stopped.
The disease was described in 1933 by Henrik Sjögren, after whom it is named; however, a number of earlier descriptions of people with the symptoms exist. Between 0.2% and 1.2% of the population are affected, with half having the primary form and half the secondary form. Females are affected about ten times as often as males and it commonly begins in middle age; however, anyone can be affected. Among those without other autoimmune disorders, life expectancy is unchanged.
- 1 Signs and symptoms
- 2 Causes
- 3 Pathogenesis
- 4 Diagnosis
- 5 Prevention
- 6 Treatment
- 7 Prognosis
- 8 Epidemiology
- 9 History
- 10 Research
- 11 Notable cases
- 12 References
- 13 External links
Signs and symptoms
The hallmark symptom of SS is dry mouth and keratoconjunctivitis sicca (dry eyes). Vaginal dryness and dry skin and dry nose may also occur. Other organs of the body may also be affected including kidneys, blood vessels, lungs, liver, pancreas, and brain.
Skin dryness in some people with SS may be the result of lymphocytic infiltration into skin glands. The symptoms may develop insidiously, with the diagnosis often not considered for several years, because the complaints of sicca may be otherwise attributed to medications, a dry environment, aging, or may be regarded as not of severity warranting the level of investigation necessary to establish the presence of the specific underlying autoimmune disorder.
SS can damage vital organs of the body with symptoms that may plateau or worsen, or go into remission as with other autoimmune diseases. Some people may experience only the mild symptoms of dry eyes and mouth, while others have symptoms of severe disease. Many patients can treat problems symptomatically. Others experience blurred vision, constant eye discomfort, recurrent mouth infections, swollen parotid glands, dysphonia (vocal disorders including hoarseness), and difficulty in swallowing and eating. Debilitating fatigue and joint pain can seriously impair quality of life. Some patients can develop renal (kidney) involvement (autoimmune tubulointerstitial nephritis) leading to proteinuria (excess protein in urine), urinary concentrating defect, and distal renal tubular acidosis.
Among the complications discussed above, women with anti-Ro/SS-A and anti-La/SS-B antibodies who become pregnant, have an increased rate of neonatal lupus erythematosus with congenital heart block requiring a pacemaker. Type I cryoglobulinemia is a known complication of SS.
SS is associated with a number of other medical conditions, many of which are autoimmune or rheumatic disorders, such as celiac disease, fibromyalgia, SLE (lupus), autoimmune thyroiditis, multiple sclerosis and spondyloarthropathy, and several malignancies, principally non-Hodgkin lymphoma.
The cause of SS is unknown, but it may be the influence of a combination of genetic, environmental, and other factors—as is the case with many other autoimmune disorders.
The observation of high rates of autoimmune disorders in families of SS is linked with a genetic predisposition to the syndrome. Studies on the polymorphisms of human leukocyte antigen (HLA)-DR and HLA-DQ gene regions in SS patients show differential susceptibility to the syndrome due to different types of the resulting autoantibody production.
Since SS is associated with a high prevalence in women, sex hormones, especially estrogen, are believed to affect humoral and cell-mediated immune responses affecting susceptibility to the syndrome. Androgens are generally considered to prevent autoimmunity. Studies on mice models suggest estrogen deficiency stimulates presentation of autoantigens, inducing SS-like symptoms.
Microchimerism of fetal cells (offspring lymphoid cells in maternal circulation) may generate autoimmunity in women who have been previously pregnant. Generation of an autoimmune potential via microchimerism may lead to a switch from a silent form of autoimmunity with age-dependent decrease in self-tolerance.
Viral proteins, engulfed molecules, or degraded self-structures may initiate autoimmunity by molecular mimicry and increase the chances of SS development. Epstein-Barr virus, hepatitis C, and human T-cell leukemia virus-1 are among the most studied infectious agents in SS. Damaged self-structures targeted for apoptosis may be mistakenly exposed to the immune system, triggering autoimmunity in exocrine glands, which are often prone to autoimmune responses.
The pathogenetic mechanisms of SS have not been fully elucidated, resulting in the lack of pathophysiology knowledge of the management of this autoimmune exocrinopathy. Although the numerous factors contributing to the progression of this disease have made it difficult to find out the exact origin and cause, major advances over the past decade have contributed to a proposed set of pathogenic events that occur prior to the diagnosis of SS.
SS was originally proposed as a specific, self-perpetuating immune system-mediated loss of exocrine glands, specifically acinar and ductal cells. Although this explains the more obvious symptoms (e.g., the lack of salivary and lacrimal fluid), it does not explain the more widespread systemic effects seen in the progression of the disease.
In the presence of a susceptible genetic background, both environmental and hormonal factors are thought capable of triggering the infiltration of lymphocytes, specifically CD4+ T cells, B cells, and plasma cells, causing glandular dysfunction in the salivary and lacrimal glands.
SS is associated with increased levels in cerebrospinal fluid (CSF) of IL-1RA, an interleukin 1 antagonist. This suggests that the disease begins with increased activity in the interleukin 1 system, followed by an autoregulatory up-regulation of IL-1RA to reduce the successful binding of interleukin 1 to its receptors. Interleukin 1 likely is the marker for fatigue, but increased IL-1RA is observed in the CSF and is associated with increased fatigue through cytokine-induced sickness behavior. SS, though, is characterized by decreased levels of IL-1ra in saliva, which could be responsible for mouth inflammation and dryness. Patients with secondary SS also often exhibit signs and symptoms of their primary rheumatic disorders, such as systemic lupus erythematosus, rheumatoid arthritis, or systemic sclerosis.
The genetic locus most significantly associated with primary SS is the major histocompatibility complex/human leukocyte antigen (MHC/HLA) region, as demonstrated by the preliminary results of the first genome-wide association study (GWAS). This GWAS included data from a discovery cohort of 395 patients of European ancestry with primary SS, and 1,975 healthy control individuals, and from a replication study that comprised 1,234 cases and 4,779 healthy controls. Associations with polymorphisms located at six independent loci were also detected; IRF5, STAT4, BLK, IL12A, TNIP1, and CXCR5. This also suggested the activation of the innate immune system, notably through the IFN system, B-cell activation through CXCR5-directed recruitment to lymphoid follicles and B-cell receptor (BCR) activation involving BLK, and T-cell activation owing to HLA susceptibility and the IL-12-IFN-γ-axis.
Patients of different ethnic origin carry different HLA susceptibility alleles, of which, HLA-DR and HLA-DQ are involved in the pathogenesis of SS. For example, patients from Northern and Western Europe and from North America show a high prevalence of B8, DRw52, and DR3 genes. HLA class II alleles are associated with the presence of specific subsets of autoantibodies, rather than with the disease itself. Autoantibodies refer to the loss of B-cell tolerance leading to production of antibodies directed against diverse organ-specific and organ nonspecific antigens. Association between HLA and SS is restricted to patients with anti-SSA/Ro or anti-SSB/La antibodies. Seropositivity for anti-Ro and anti-La is associated with greater severity and longer duration of disease, and findings of their high abundance from the salivary glands of SS patients suggests their imperative role in the pathogenesis of SS.
Beyond genetics, epigenetic abnormality related to DNA methylation, histone acetylation, or microRNA expression probably have key roles in the pathogenesis of autoimmune diseases, including SS, though research in this area is very limited and minimal.
Environmental factors, such as glandular viral infection, could prompt epithelial cells to activate the HLA-independent innate immune system through toll-like receptors. Although a number of infectious, exogenous agents have been implicated in the pathogenesis of SS, such as Epstein-Barr virus (EBV), human T-lymphotropic virus 1, and hepatitis C virus, their association with SS appears weak. While EBV is present in the salivary glands of normal individuals, a high incidence of EBV reactivation in SS patients has been reported with increased levels of EBV DNA. This indicates viral reactivation and inability of lymphoid infiltrates to control EBV replication in SS, leading to the initiation or perpetuation of an immune response in target organs. Nonetheless, it remains to be clarified exactly how reactivation of EBV is induced in lesions of patients with SS, and which specific molecular mechanisms are involved in the process of viral reactivation.
Epithelial cells in SS lesions are active participants in the induction and perpetuation of the inflammatory process. Environmental and hormonal factors, in concert with an appropriate genetic background, are believed to trigger SS, which dysregulates epithelial cells and allows aberrant homing and activation of dendritic cells (DCs), T cells, and B cells. Dendritic cells are antigen-presenting cells which process antigen material and present it to other T cells. Following the migration of lymphocytes into the glands in response to chemokines and specific adhesion molecules, T cells interact with epithelial cells. Epithelial cells are further activated by proinflammatory cytokines (IL-1β, IFN-γ, and TNF), which are produced by adjacent T cells. The early accumulation of plasmacytoid dendritic cells in the target tissues, which produce high levels of type 1 IFNs, seems important, as these cells can further dysregulate the immune response through abnormal retention of lymphocytes in the tissues and their subsequent activation. IFN-α stimulates the production of B-cell activating factor (BAFF) by epithelial cells, DCs, and T cells. BAFF stimulates aberrant B-cell maturation, leading to the emergence of self-reactive B cells, which locally produce autoantibodies, in a germinal centre-like structure (GC-like), which is also the location of lymphomagenesis (origin of lymphoma).
Programmed cell death
Dysregulation of apoptosis (programmed cell death) is believed to play a role in the pathogenesis of a variety of autoimmune diseases, though its role in SS is controversial. Both the Fas and Fas ligand proteins are overexpressed in primary SS patients, while expression of BCL-1, which is known to downregulate apoptosis, was found significantly reduced in acinar and ductal epithelial cells of SS patients compared to healthy people. In situ studies did not show increased apoptosis among glandular epithelial cells, but did show reduced apoptosis among infiltrating mononuclear cells. Reduced apoptosis was also implicated in the accumulation of autoreactive B-cells found in the glands. The relationship of autoantibodies expressed in SS with apoptosis is still being researched.
Sex hormones seem to influence humoral and cell-mediated immune response, with estrogen being considered one of the biggest factors responsible for sex-immunologic dimorphism. Estrogen deficiency appears to play a role in development of SS. It has been hypothesized that androgen administration to the ocular surface may serve as an effective therapy for dry eyes.
Diagnosing SS is complicated by the range of symptoms a patient may manifest, and the similarity between symptoms of SS and those of other conditions. Also, patients with SS symptoms approach different specialities for treatment, which can make diagnosis difficult. Since dry eyes and dry mouth are very common symptoms, and frequently occur in people over 40, people often think the symptoms are age-related and ignore them. However, some medications can cause symptoms similar to those of SS. The combination of several tests, which can be done in a series, can eventually diagnose SS.
SS is usually classified as either 'primary' or 'secondary'. Primary Sjögren syndrome occurs by itself and secondary Sjögren syndrome occurs when another connective tissue disease is present.
Blood tests can be done to determine if a patient has high levels of antibodies that are indicative of the condition, such as antinuclear antibody (ANA) and rheumatoid factor (because SS frequently occurs secondary to rheumatoid arthritis), which are associated with autoimmune diseases. Typical SS ANA patterns are SSA/Ro and SSB/La, of which Anti-SSB/La is far more specific; Anti-SSA/Ro is associated with numerous other autoimmune conditions, but are often present in SS. However, Anti-SSA and Anti-SSB tests are frequently not positive in SS.
The rose bengal test uses a stain that measures state and function of the lacrimal glands. This test involves placing the non-toxic dye rose bengal on the eyes. The dye’s distinctive colour helps in determining the state and functioning of tear film and the rate of tear evaporation. Any distinctive colour change can indicate SS, but confirming the condition requires many related diagnostic tools.
Schirmer's test measures the production of tears: a strip of filter paper is held inside the lower eyelid for five minutes, and its wetness is then measured with a ruler. Producing less than 5 mm (0.20 in) of liquid is usually indicative of SS. This measurement analysis varies among people depending on other eye-related conditions and medications in use when the test is taken. A slit-lamp examination can reveal dryness on the surface of the eye.
Symptoms of dry mouth and dryness in the oral cavity are caused by the reduced production of saliva from the salivary glands (parotid gland, submandibular gland, and sublingual gland). To check the status of salivary glands and the production of saliva, a salivary flow-rate test is performed, in which the person is asked to spit as much as they can into a cup, and the resulting saliva sample is collected and weighed. This test's results can determine whether the salivary glands are functioning adequately. Not enough saliva produced could mean the person has SS. An alternative test is non-stimulated whole saliva flow collection, in which the person spits into a test tube every minute for 15 minutes. A resultant collection of less than 1.5 ml (0.053 imp fl oz; 0.051 US fl oz) is considered a positive result.
A lip/salivary gland biopsy takes a tissue sample that can reveal lymphocytes clustered around salivary glands, and damage to these glands due to inflammation. This test involves removing a sample of tissue from a person’s inner lip/salivary gland and examining it under a microscope. In addition, a sialogram, a special X-ray test, is performed to see if any blockage is present in the salivary gland ducts (i.e. parotid duct) and the amount of saliva that flows into the mouth.
Also, a radiological procedure is available as a reliable and accurate test for SS. A contrast agent is injected into the parotid duct, which opens from the cheek into the vestibule of the mouth opposite the neck of the upper second molar tooth. Histopathology studies should show focal lymphocytic sialadenitis. Objective evidence of salivary gland involvement is tested through ultrasound examinations, the level of unstimulated whole salivary flow, a parotid sialography or salivary scintigraphy, and autoantibodies against Ro (SSA) and/or La (SSB) antigens.
SS can be excluded from people with past head and neck radiation therapy, acquired immunodeficiency syndrome (AIDS), pre-existing lymphoma, sarcoidosis, graft-versus-host disease, and use of anticholinergic drugs.
There is no prevention mechanism for SS due to its complexity as an autoimmune disorder. However, lifestyle changes can reduce the risk factors of getting SS or reduce the severity of the condition with patients who have already been diagnosed. Diet is strongly associated with inflammation that is mostly seen in many autoimmune related diseases including SS. An experimental study concludes that SS patients show high sensitivity to gluten that directly relates to inflammation. Moderate exercise is also helpful in SS patients, mainly reducing the effect of lung inflammation.
Neither a cure for SS nor a specific treatment is known to permanently restore gland secretion. Instead, treatment is generally symptomatic and supportive.
Moisture replacement therapies such as artificial tears may ease the symptoms of dry eyes. Some patients with more severe problems use goggles to increase local humidity or have punctal plugs inserted to help retain tears on the ocular surface for a longer time.
Additionally, cyclosporine (Restasis) is available by prescription to help treat chronic dry eye by suppressing the inflammation that disrupts tear secretion. Prescription drugs are also available that help to stimulate salivary flow, such as cevimeline (Evoxac) and pilocarpine. Salagen, a manufactured form of pilocarpine, can be used to help produce tears, as well as saliva in the mouth and intestines. It is derived from the jaborandi plant.
In women with SS, vaginal dryness, vulvodynia and dyspareunia (painful sexual intercourse) are often reported; personal lubricants are recommended to help lessen irritation or pain that may result from dryness in the vaginal and vulva areas.
Nonsteroidal anti-inflammatory drugs (NSAIDs) may be used to treat musculoskeletal symptoms. For individuals with severe complications, corticosteroids or immunosuppressive drugs may be prescribed, and sometimes IVIG (intravenous immunoglobulin). Also, disease-modifying antirheumatic drugs (DMARDs) such as methotrexate may be helpful. Hydroxychloroquine (Plaquenil) is another option and is generally considered safer than methotrexate. However, these prescribed drugs have a range of side effects such as nausea, loss of appetite, dizziness, hair loss, stomach aches/cramps, headache, liver toxicity, and increased risk of infections. Also, people who take drugs to suppress the immune system are more likely to develop cancer later.
For systemic symptoms, including fatigue, joint pain, myositis and neuropathy, biologic immunosuppressant drugs such as rituximab and belimumab that work via B-cell pathology are often used and have less toxic profiles than traditional immunosuppressive regimens.
Preventive dental treatment is also necessary (and often overlooked by the patient), as the lack of saliva associated with xerostomia creates an ideal environment for the proliferation of bacteria that cause cavities. Treatments include at-home topical fluoride application to strengthen tooth enamel and frequent teeth cleanings by a dental hygienist. Existing cavities must also be treated, as cavities that extend into the tooth can not be effectively treated through teeth cleaning alone, and are at a high risk of spreading into the pulp of the tooth, leading to the loss of vitality and need for extraction or root canal therapy. This treatment regimen is the same as for all xerostomia patients—such as those undergoing head and neck radiation therapy, which often damages the salivary glands, which are more susceptible to radiation than other body tissues.
Published studies on the survival of SS patients are limited in varied respects, perhaps owing to the relatively small sample sizes, and secondary SS is associated with other autoimmune diseases. However, results from a number of studies indicated, compared to other autoimmune diseases, SS is associated with a notably high incidence of malignant non-Hodgkin lymphoma (NHL). NHL is the cancer derived from white blood cells. About 5% of patients with SS develop some form of lymphoid malignancy. Patients with severe cases are much more likely to develop lymphomas than patients with mild or moderate cases. The most common lymphomas are salivary extranodal marginal zone B cell lymphomas (MALT lymphomas in the salivary glands) and diffuse large B-cell lymphoma.
Lymphomagenesis in primary SS patients is considered as a multistep process, with the first step being chronic stimulation of autoimmune B cells, especially B cells that produce rheumatoid factor at sites targeted by the disease. This increases the frequency of oncogenic mutation, leading to any dysfunction at checkpoints of autoimmune B-cell activation to transform into malignancy. A study's finding has concluded the continuous stimulation of autoimmune B cells, leading to subtle germinal abnormalities in genes having specific consequences in B cells, which underlies the susceptibility to lymphoma.
Apart from this notably higher incidence of malignant NHL, SS patients show only modest or clinically insignificant deterioration in specific organ-related function, which explains the only slight increases in mortality rates of SS patients in comparison with the remainder of the population.
SS is the second most common rheumatic autoimmune disorder, behind rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). There are no geographical differences in the rates of SS. SS has been reported in all areas of the world, although regional rates have not been well studied. Depending on the criteria for determining prevalence, studies estimate the prevalence of SS at 500,000 to 2 million people in the United States. Moreover, other broader studies of prevalence of SS range widely with some reports of up to a prevalence of 3% of the population. A few studies that have been conducted on the incidence of SS report that the incidence of the syndrome varies between 3 and 6 per 100,000 per year.
Nine out of ten SS patients are women. In addition to prevalence in women, having a first-degree relative with an autoimmune disease and previous pregnancies have been identified as epidemiological risk factors. Differences in prevalence due to race and ethnicity are unknown.
Although SS occurs in all age groups, the average age of onset is between ages 40 and 60, although experts note that up to half of all cases may be left undiagnosed or unreported. The prevalence of SS generally increases with age.
SS is reported in 30-50% of people with rheumatoid arthritis and 10-25% with systemic lupus erythematosus.
Jan Mikulicz-Radecki (1850–1905) is generally credited with the first description of SS. In 1892, he described a 42-year-old man with enlargement of the parotid and lacrimal glands associated with a round-cell infiltrate and acinar atrophy. However, the criteria Mikulicz established for diagnosis, often led to misdiagnosis of Mikulicz’s syndrome. Many conditions, such as tuberculosis, infections, sarcoidosis, and lymphoma present with similar conditions to those listed under Mikulicz’s syndrome. Nevertheless, the term "Mikulicz’s syndrome" is still used occasionally to describe the appearance of lymphocytic infiltrates on salivary-gland biopsies.
In 1930, Henrik Sjögren (1899–1986), an ophthalmologist in Jönköping, Sweden, observed a patient with low secretions from the lacrimal and salivary glands. Sjögren introduced the term keratoconjunctivitis sicca for the symptom of dry eyes (keratoconjunctivitis). In 1933, he published his doctoral thesis, describing 19 females, most of whom were postmenopausal and had arthritis, showing clinical and pathological manifestations of the syndrome. Sjögren clarifies that keratoconjunctivitis sicca, resulting from water deficiency, had no relation to xerophthalmia, resulting from vitamin A deficiency. Sjögren's thesis was not well received as the Board of Examiners criticized some clinical aspects.
After extensive research and data collection, Sjögren published an essential paper in 1951, describing 80 patients with keratoconjunctivitis sicca, 50 of whom also had arthritis. His subsequent follow-up conference trips pertaining to his paper led to an international interest in SS. The term keratoconjunctivitis sicca was coined by Sjögren himself and began to be identified as SS in literature, although it can now have more general usage.
Research on multifactorial autoimmune diseases such as SS focuses on expanding the knowledge surrounding the disorder, improving diagnostic tools and finding ways to prevent, manage, and cure the disorder. The United Kingdom Primary Sjögren's Syndrome Registry, a tissue biobank of samples taken for research, supported by the Medical Research Council, UK was established in 2010.
As an autoimmune disease, susceptibility to SS is greatly influenced by the human leukocyte antigen. DQA1*05:01, DQB1*02:01, and DRB1*03:01 alleles were identified as risk factors, while DQA1*02:01, DQA1*03:01 and DQB1*05:01 alleles were found to be protective factors for the disease. The relationship between alleles and specific race was also established. HLA-DQ2 and HLA-B8 are generally found in Caucasian patients, while HLA-DR5 is related to Greek and Israeli patients. Multiple genome-wide association scans may be conducted in the future to identify key risk variants.
Viruses that can trigger the immune response of the syndrome include human T-lymphotropic virus type 1 (HTLV-1), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV) and hepatitis C virus (HCV). The UK Primary Sjögren's Syndrome Registry supports clinical trials and genetic studies of SS and is open to people wishing to participate in research studies and researchers studying the disease.
Some research showed that the lack of vitamin A and vitamin D are associated with this disease. Vitamin D deficiency was found to be related to neurological manifestations and the presence of lymphoma among patients. On the other hand, vitamin A levels were inversely associated with extra-glandular manifestations of the disease.
Saliva is a potential diagnostic tool of SS because the salivary component is changed after onset of the disease. With the new miniaturization technology, called ‘lab on a chip’, the diagnosis can be more convenient.
With regard to therapeutics, multiple monoclonal antibodies were under investigation in 2007. The most promising seemed to be the anti-CD20 rituximab and the anti-CD22 epratuzumab, while the anti-TNF-α and IFN-α seemed less effective.
In 2014, the Sjögren's Syndrome Foundation announced a five-year goal to cut the time to diagnoses in half.
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|Wikimedia Commons has media related to Sjögren's syndrome.|
- Sjögren syndrome at NHS Choices
- Sjögren syndrome – US National Institute of Arthritis and Musculoskeletal and Skin Diseases
- Price, EJ; Rauz, S; Tappuni, AR; Sutcliffe, N; Hackett, KL; Barone, F; Granata, G; Ng, WF; Fisher, BA; Bombardieri, M; Astorri, E; Empson, B; Larkin, G; Crampton, B; Bowman, SJ; British Society for Rheumatology Standards, Guideline and Audit Working, Group. (1 October 2017). "The British Society for Rheumatology guideline for the management of adults with primary Sjögren's Syndrome". Rheumatology. 56 (10): e24–e48. doi:10.1093/rheumatology/kex166. PMID 28957550.