Sjögren disease,new name,new guidelines: Key messages for primary care

Abstract

Sjögren’s syndrome is increasingly renamed Sjögren disease, as in the recent British Society of Rheumatology guidelines. These guidelines provide evidence-based recommendations for the management of adult and juvenile onset Sjögren disease. Sjögren disease is the second most common autoimmune rheumatic disease (after rheumatoid arthritis), affecting approximately 0.6% of adults, over 90% of whom are women. Sjögren disease can occur as a stand-alone autoimmune disease or overlap with other conditions such as rheumatoid arthritis, systemic lupus erythematosus or systemic sclerosis. This article aims to highlight the salient features of the guidelines for primary care physicians to improve the early diagnosis of Sjögren disease and inform the day-to-day management of established cases. The two clinical case scenarios featured in this article should help to highlight the importance of early diagnostic pick up whilst minimising false positive diagnosis and to highlight key messages from the new guidelines. A summary sheet of these guidelines is included in the supplementary material.

Clinical case scenario 1

A 25-year-old woman with a past medical history (PMH) of hypothyroidism (stable on 100 mcg levothyroxine) and non-ulcer dyspepsia gives a 6-month history of fatigue, mainly physical in nature, with intermittent knee and wrist pains, but no early morning stiffness. She also reports a ‘gritty feeling’ in her eyes and a dry mouth, especially in the morning. There are no psychosocial yellow flags and her PHQ9 and GAD7 scores of five and 11 respectively, are unremarkable. She also describes intermittent feverish symptoms. A maternal aunt has rheumatoid arthritis.

What is your differential diagnosis here? Do you think the symptoms and history are coincidental or do they fit with a coherent diagnosis? You are unsure of the diagnosis but, because of the fatigue, you order the blood tests recommended in the Royal College of Physicians (RCP) fibromyalgia guidelines 2022 (RCP, 2022). These are: Full blood count, erythrocyte sedimentation rate, liver function tests, urea and electrolytes, C-reactive protein, creatine kinase, thyroid stimulating hormone and blood glucose.

Significant abnormalities are as follows: Haemoglobin =110 g/L, total white count = 2.8, ESR 40 mm/h, CRP 8. You are surprised by the results, especially the raised ESR, and are concerned about a systemic disease, possibly a connective tissue disorder. You request an antinuclear antigen (ANA) and rheumatoid factor (RF). The family history of rheumatoid arthritis is noteworthy; the heritability of connective tissue diseases is complex and beyond the scope of this article, but is nevertheless a factor to consider here.

Choosing wisely when to request an antinuclear antibody test

It is worth briefly considering ANA at this point, as it is context-specific and should not be requested without good reason. ANA is usually reported quantitatively as a titre; 1:1280, for example, would be considered strongly positive. With a significantly positive ANA most labs do more specific staining techniques to delineate extractable nuclear antigens (ENA). Anti-Ro (named after the original patient from whom it was extracted) is one such ENA and is considered a key marker for Sjögren disease (Price et al., 2024). Box 1 gives useful tips and advice about ‘choosing wisely’ when requesting ANA (Ferrari, 2015). Box 2 lists possible markers in the history and examination which may suggest a possible connective tissue disease. Box 1.
ANA testing - choosing wisely – to do or not to do?

Request if connective tissue disease is suspected (see Box 2 for a list of possible markers in history)

Remember – positive ANA needed to progress to ENA (labs usually decide this) – although the BSR guidelines suggest that still requesting anti-Ro antibodies if there is a strong suspicion of Sjögren disease in presence of negative ANA

ANA – sensitivity for Sjögren disease = 58–85%, specificity = 50–97% (from BSR guidelines)

Anti Ro sensitivity 89–92% specificity 71–77% (currently our best blood biomarker for Sjögren disease)

Not as part of FMS work-up unless specific suggestion of connective tissue disease (bearing in mind comorbid FMS in many connective tissue disease patients) - British and North American rheumatology societies recommend not requesting ANA just for fatigue or malaise in absence of suspicion of connective tissue disease

Highly sensitive for connective tissue disease, but low specificity (reduces utility for nonspecific symptoms) – BSR recommend that isolated positive ANA/ENA tests should be dealt with by A&G if available

Remember – low levels of ANA occur in normal individuals e.g. 1:40 titre occurs in 30–40% normal population (increasing with age and with drugs such as phenytoin, terbinafine, chlorpromazine)

Usual cut off for lab reporting positive is greater than 1:160

Higher titre such as 1:1280 more significant

Positive predictive value is greatly enhanced by high pre-test probability of connective tissue disease

Box 2.
Connective tissue disease – potential markers.

Photosensitivity

Joint or muscle pains

Mouth ulcers

Sicca symptoms (dry eyes, dry mouth)

Raynaud’s phenomenon

Dyspnoea/pleurisy

Recurrent miscarriage

Atypical rashes

Scarring alopecia

Proteinuria

Haemolytic anaemia

The ANA results are as follows: ANA positive at 1:1280; ENA – anti-Ro positive. RF was also reported as positive. The strongly positive ANA (high titre) provides good proof of autoimmunity. For lower titres with no raised inflammatory markers in the absence of significant connective tissue disease features the British Society of Rheumatology 2024 guidelines recommend the use of an advice and guidance pathway if available. The combination of mild normochromic anaemia, lymphopenia, raised ESR with normal or low CRP is a common constellation in connective tissue diseases such as Sjögren disease or lupus. Given that there was no early morning stiffness, joint swelling or warmth you did not think the arthralgia fitted with an inflammatory arthritis. Paradoxically the positive RF might trigger a referral to an early synovitis clinic, but positive RF is common in Sjögren disease, even in the absence of rheumatoid (positive in about half of patients with Sjögren disease).

The common age group for presentation and the female preponderance of Sjögren disease overlaps significantly with fibromyalgia syndrome (FMS) and it is estimated that 30% of patients with Sjögren disease have FMS symptoms (even though the overall adult prevalence of FMS is only 2%). Fatigue is a complex and multifaceted concept, and a key GP skill is to be able to distinguish functional elements of fatigue (e.g. ‘fibrofog’) from inflammatory elements. The fatigue in Sjögren disease is thought to be at least in part driven by type I interferons and pro-inflammatory cytokines, much like a viraemia, whereas the fatigue in FMS is thought to be related to central and peripheral nervous system sensitisation with no currently identifiable biomarkers. In this case, the absence of chronic widespread pain and probable low-grade fevers would make FMS unlikely.

Sjögren disease is a multisystem disease associated with as severe a symptom burden as rheumatoid and lupus; it is far from being a benign illness (Miyamoto et al., 2021). An average patient with Sjögren disease has a diagnostic odyssey of 3 to 6 years to obtain a correct diagnosis (Meinecke et al., 2024). Given the severe, often hidden, morbidity and the risk of multisystem complications, patients with Sjögren disease deserve a more streamlined journey. Sjögren disease is likely to present in 90% of cases with sicca symptoms (dry mouth, dry eyes, and other mucous membranes) and/or fatigue (estimated to affect 75% of patients). However, dry eyes and dry mouth are both very common in the general population affecting an estimated 8–34% of adults; only a small percentage of these patients will have Sjögren disease. Fatigue is also a very common problem in primary care and is reported as the main presenting symptom in 5–10% of patients, and yet the average GP may only see a patient with new Sjögren disease every 6–8 years.

This clinical scenario is strongly suggestive of Sjögren disease and this patient should be referred to rheumatology. The BSR guidelines remind us that to make a diagnosis of Sjögren disease in accordance with the 2016 ACR/EULAR (American College of Rheumatology/European League Against Rheumatism) criteria for adult Sjögren disease. A score of four or more is needed (Shiboski et al., 2017). The anti-Ro positivity scores three, but it is not practicable in primary care to do any of the other tests (ocular staining score), Schirmer’s test, unstimulated whole salivary flow, lip biopsy (focus score)). Pragmatically, then, a positive anti-Ro is the GP’s best way of picking up Sjögren disease, together with a good history. The BSR guidelines state that despite the development of novel antibody markers for Sjögren disease none outperforms anti-Ro. It is worth remembering that patients may not describe their eye symptoms as ‘dry’ but use expressions such as ‘gritty’ ‘sore’ or ‘tired’. Although ANA will usually be positive if anti-Ro antibodies are positive, this is not always the case; and if the history is strongly suggestive of Sjögren disease with a negative ANA, it is still worth requesting ENA to pick up a positive anti-Ro (you may need to discuss this rationale with the laboratory to avoid the request being rejected).

The importance of not missing Sjögren disease in children and young adults

This patient’s relatively young age is a reminder that Sjögren disease can present in childhood, adolescence and young adulthood, as well as the classic middle-aged female presentation. It is very important that this type of presentation in a young adult is not missed because young age of onset, with positive anti Ro and RF carries an increased risk of extra glandular complications including a long-term risk of lymphoma. Most Sjögren disease-associated lymphomas are of the non-Hodgkin B cell type, mainly affecting the salivary glands and the BSR guidelines remind us that there is a 5–10% lifetime risk (Ramos-Casals et al., 2014). Indeed, this patient mentioned low grade fevers and certainly if she continued with these or developed pruritus, weight loss, night sweats and swelling of salivary glands, especially the parotid gland, an urgent referral to haematology would be indicated (National Institute for Health and Care Excellence (NICE), 2015a). The presence of anti-Ro in this patient is a marker for increased risk of neonatal lupus and foetal heart block in any future pregnancies and it is important to counsel this patient about risk and possible mitigation (she may need low-dose aspirin in pregnancy and consideration of hydroxychloroquine during pregnancy and foetal intrapartum heart monitoring and should be referred early for consultant-led antenatal care).

Diseases such as hypothyroidism (20%) and coeliac disease (4%) are more common in Sjögren disease. This patient already has hypothyroidism and the BSR guidelines advise testing for coeliac disease as part of the work up. Although there are, to date, no national screening recommendations for coeliac disease (NICE, 2015b), Coeliac UK provide quite a long list of scenarios where coeliac disease testing is recommended. They also point out that only 36% of UK patients with coeliac disease are currently diagnosed, and the average delay in diagnosis is 13 years. The previous diagnosis of non-ulcer dyspepsia in this patient may well also be related to Sjögren disease, as heartburn and oesophageal dysfunction are common. Remember also that Sjögren disease is essentially an autoimmune exocrinopathy – hence, reduced function of glands including salivary, lacrimal, meibomian and submucosal glands of nose, pharynx, larynx, large airways and vagina- all of which may be symptomatic (Al-Ezzi, et al., 2017).

Clinical case scenario 2

A 55-year-old woman presents with a new history of dry eyes. Her optometrist recently gave her hyaluronic acid eye drops which have helped and she requests a repeat prescription for these. Her PMH includes mild Raynaud’s phenomenon, total abdominal hysterectomy, and an episode of renal colic last year. You notice that she is carrying a small water bottle and she confesses to carrying this everywhere due to her very dry mouth which has been present for several years but she thinks this was made worse when she was given solifenacin 5 mg daily for overactive bladder. She is also on sertraline 50 mg daily, which was started for mild anxiety and fatigue (also partly attributed to her menopause). She has been on hormone replacement therapy in the form of estradiol patch 50 mcg/24 h for several years and this really helped her flushes and palpitations, but not her vaginal dryness and she still sleeps poorly.

What features of this patient’s sicca symptoms might suggest possible Sjögren disease? Over 7,000,000 prescriptions are issued annually in England for dry eyes – the vast majority of these will not have Sjögren disease. The incidence of dry eyes and dry mouth increases with age, various conditions and importantly many drugs. In this context a useful concept is that of anticholinergic burden (ACB). This refers to the cumulative effect of using multiple medications with anticholinergic properties. It is important to know which commonly used drugs are associated with a high ACB score, as not only can these cause dry mouth, but also confusion and cognitive impairment. Knowledge of the commonly prescribed high ACB drugs is useful in identifying iatrogenic causes; such high ACB drugs include antidepressants, antihistamines, cough suppressants, medications for overactive bladder syndrome, to name but a few.

In this case you consult one of the many anticholinergic burden tools available online (for example, Health Care Improvement Scotland right decision service: Anticholinergics). You note that solifenacin has an ACB score of three and sertraline a score of two giving a cumulative ACB of five. She thinks that the solifenacin is not really helping her overactive bladder, so you switch this to a zero ACB alternative, mirabegron 50 mg daily (she is normotensive). You establish that the sertraline she has been on for several years is not really helping her anxiety or fatigue; she is not depressed, so you ask her to halve the sertraline to tail it off. You also give her a prescription for estradiol vaginal tablets 10 mcg daily for 2 weeks, dropping to twice weekly and ask her to rebook a follow up appointment in 4–6 weeks.

When she re-attends, her mouth, eye, fatigue, overactive bladder and vaginal symptoms are no better. What do you do next? You decide to do some bloods: FBC ESR ANA U&ES LFTS TFT CRP HbA1c CRP vitamin D. You include an ANA because of the previous Raynaud’s phenomenon, sicca symptoms and fatigue. Significant results were as follows: Hb = 109 g/L, ESR = 60, CRP = 11, ANA positive 1:640, Vitamin D (1,25) = 40 µmol/L, anti-Ro positive, potassium = 3.2 mmol/L, bicarbonate 19 mmol/L, alanine transferase (ALT) = 55 IU.

There are several valuable learning points in this case. First, the combination of symptoms with positive ANA and anti-Ro, with raised inflammatory markers is again very suggestive of Sjögren disease and this patient will require referral to rheumatology. Following the BSR guidelines, given the raised ESR you may decide to go on to do some of the other bloods and it would not be unusual to identify a monoclonal gammopathy which is found in around 20% of patients with Sjögren disease (Brito-Zeron et al., 2012). The combination of slightly low potassium and low bicarbonate may suggest distal renal tubal acidosis which is present in 10–40% of patients with Sjögren disease. The previously reported renal stone could also be related to this renal abnormality. The slightly raised ALT could be related to alcohol, medications or fatty liver disease, but it is also worth noting that autoimmune liver disease such as primary biliary cholangitis (previously called primary biliary cirrhosis) occurs in Sjögren disease (5%) and abnormal LFTS are present in around 40%.

Another important learning point here is to beware of insidious disease presentations falsely attributed to the menopause. It is worth remembering that FMS and connective tissue diseases such as Sjögren disease commonly develop during the perimenopausal period. The failure of the vaginal dryness to respond to both systemic and topical oestrogens may suggest a non-hormonal cause of dryness (i.e. Sjögren disease) and the need to prescribe a vaginal moisturiser. The overactive bladder symptoms previously treated with anticholinergics may have been due to non-hormonal vaginal dryness all along. Low Vitamin D is common in latitudes above 40° north including the UK (30% of adults) with some evidence that low levels are associated with worse dry eye parameters. The slightly low levels here (in the insufficiency range) might just need lifestyle, diet, or over-the-counter vitamin D advice.

Primary care role in ongoing management of established Sjögren disease patients

It is clearly frustrating for patients with Sjögren disease and clinicians alike that there is currently no significantly effective disease-modifying therapy (the BSR guidelines examine this in detail). The rapid progress made in the fields of artificial intelligence, immunology and genomics promise better treatments in the future. Many large rheumatology departments now have multidisciplinary ‘one stop’ clinics reflecting the multisystem nature of Sjögren disease. GPs are likely to need to work closely with rheumatology to provide personalised treatment for Sjögren disease patients tailored to their individual symptom burdens. Small individual gains from multiple interventions can collectively improve these patients’ quality of life. The BSR guideline summary sheet gives a succinct list of lifestyle advice. The primary care clinician is in a key position to support patients along these lines. Examples might include providing access to NHS-funded sleep and mental health smartphone applications, exercise programmes and providing documentation for workplace modifications. It is also important to acknowledge the ‘hidden morbidities’ of Sjögren disease which may not be apparent to employers, and for the clinician to be aware of ‘presenteeism’ factors in assessing any need for sickness certification.

The primary care team has a crucial role in facilitating prescriptions for the various secretory replacements used in Sjögren disease. Artificial tears are very safe, should be preservative free (especially free from benzalkonium chloride). Ideally, they should be used frequently (2–3 hourly) combined with a suitable preservative-free overnight eye ointment. Hyaluronic acid-based drops are generally effective, but because of severity of dry eyes in Sjögren disease some patients will be under ophthalmology care and specialists may suggest prescribing more complex tear formulations (e.g. lipid-containing eye drops or liposomal sprays) reflecting the multilayer composition of physiologically normal tears. They may even be prescribed short courses of topical steroid, topical ciclosporin and even autologous or allogenic serum eye drops. The GP should carefully consider whether generic formulary substitutions are appropriate in such patients and generally stick to specialist suggestions, as patients with Sjögren disease are at greater risk of severe eye disease including corneal melt and even perforation. Use of daily heated eyelid compresses as per the BSR guidelines is also strongly recommended.

Some patients with Sjögren disease may also require prescribed saliva substitutes and some will be on pilocarpine as a secretagogue (usually initiated by rheumatology). These products should be continued in primary care as oral/dental complications of severe long-term xerostomia are not insignificant in patients with Sjögren disease. Over-the-counter xylitol products such as sugar-free mints and chewing gum may reduce strep mutans carriage, as well as providing symptomatic relief. Frequent tooth brushing with high fluoride toothpaste – e.g. Duraphat® is recommended in the guidelines. This is currently prescription only and on the dental practitioners’ formulary, GPs may consider prescribing this for Sjögren disease (especially in young patients).

Thyroid disease and coeliac disease are both more common in patients with Sjögren disease (at 20% and 4%, respectively). Osteoarthritis, gastro-oesophageal reflux disease, and hypertension also appear to be more common than in age-sex matched controls in this population, and so the primary care clinician should bear these pointers in mind. The guidelines also remind us to be vigilant for lymphoma in patients with Sjögren disease, as lifetime risk is estimated to be 5–10%. Many of these are likely to present to primary care in the first instance. Lymphoma prediction is complex and covered in detail in the guidelines, but the GP should be vigilant for ‘B Symptoms’, lymphadenopathy, splenomegaly or new onset salivary gland enlargement, and follow the NICE guidelines (NICE, 2015a) in terms of urgent referral of such presentations. A useful practice audit might be to search the practice database to see if the number of patients coded with a Sjögren disease diagnosis was close to 0.6% and perhaps also to consider putting a lymphoma risk alert on these patient records.

Key points

Sjögren disease is a multisystem disease

Sjögren disease is the second most common autoimmune rheumatic disorder

Confirmation of diagnosis should be sought with referral to a rheumatologist

Early diagnosis of Sjögren disease is important because of the high quality of life impact and risk of complications and comorbidities

Primary care has a key role in the management of sicca symptoms, tailored lifestyle advice and signposting

Vigilance for lymphoma presentations is needed

Supplemental Material

sj-pdf-1-ino-10.1177_17557380241281472 - Supplemental material for Sjögren disease, new name, new guidelines: Key messages for primary care

Supplemental material, sj-pdf-1-ino-10.1177_17557380241281472 for Sjögren disease, new name, new guidelines: Key messages for primary care by Dr Peter Glennon in InnovAiT

Footnotes

Declaration of conflicting interests

I was the GP member of the BSR group producing the newly published guidelines (Price, Benjamin, Bombardieri et al., 2024).

ORCID iD

Dr Peter Glennon

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Supplementary Material

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