TY - JOUR
AU1 - Price, Elizabeth, J
AU2 - Baer, Alan, N
AB - Abstract SS is a chronic, autoimmune disease of unknown aetiology for which there is no known curative treatment. Although dryness of the eyes and mouth are the classically described features, patients often experience drying of other mucosal surfaces and systemic manifestations, including fatigue and arthralgia. There is an association with other autoimmune diseases, especially thyroid disease, coeliac disease and primary biliary cholangitis. Systemic features may affect up to 70% and include inflammatory arthritis, skin involvement, haematological abnormalities, neuropathies, interstitial lung disease and a 5–10% lifetime risk of B cell lymphoma. Treatment should aim to empower patients to manage their condition; conserve, replace and stimulate secretions; prevent damage; and suppress underlying systemic disease activity. Sjögren’s, guideline, management, sicca Rheumatology key messages SS is a chronic, auto-immune disease for which there is no known curative treatment. SS causes drying of eyes, mouth and other mucosal surfaces and systemic manifestations, including fatigue and arthralgia. Treatment of SS should aim to conserve, replace and stimulate secretions; prevent damage; and suppress underlying systemic disease activity. Guidelines for the management of Sjögren’s syndrome SS is a chronic, autoimmune disease of unknown aetiology for which there is no curative treatment [1]. Mucosal dryness is accompanied by systemic features including inflammatory arthritis, skin involvement, haematological abnormalities, neuropathies, interstitial lung disease and a 5–10% lifetime risk of B cell lymphoma [2, 3]. A number of practical management guidelines based on systematic reviews and involving both experts and patients have been published over the past decade (see Table 1 [4–10]). The North American, patient-led, Sjögren’s Syndrome Foundation (SSF) was involved in at least four of these, one each focusing on the mouth, eye and systemic disease and another covering a broader remit [4–7]. In all cases, a thorough systematic review was followed by a Delphi exercise to determine the final recommendations. The decision groups included health professionals and patients. The oral management guideline [4] concluded that there was strong evidence to recommend the use of topical fluoride in all patients with SS; weak evidence to recommend increasing salivation by gustatory, masticatory or pharmaceutical means; weak evidence to recommend chlorhexidene; and moderate evidence to consider using non-fluoride remineralizing agents as adjunctive therapy. The dry eye guideline [5] recommended escalating treatment based on severity and clinical manifestations and included environmental and dietary modification, the use of artificial tears, anti-inflammatory therapy and physical interventions. There was good evidence supporting the use of topical tear replacement and lubrication with preservative-free preparations; good evidence supporting the short-term use of topical corticosteroids and longer term use of topical ciclosporin; moderate evidence supporting the use of oral omega-3 essential fatty acid supplements; good evidence supporting the use of topical azithromycin, liposomal spray, oral doxycycline and manual expression to treat meibomian gland disease; good evidence for the use of punctal plugs, permanent punctual occlusion and moisture chamber glasses to preserve secretions and reduce evaporative tear loss; good evidence for oral secretagogues; good evidence for therapeutic contact lenses; good evidence for autologous serum tears; good evidence for eyelid surgery to narrow the interpalpebral fissure; but only moderate evidence for systemic anti-inflammatory therapy in the treatment of eye disease. Carsons et al. [7] focused on systemic disease, particularly the management of fatigue, musculoskeletal pain and the use of biologic agents. For musculoskeletal pain, they recommended HCQ as first line treatment followed by MTX either alone or as additional therapy. They recommended short courses of oral corticosteroids followed by the addition of leflunomide, sulfasalazine, azathioprine or ciclosporin in refractory disease, although they acknowledged the evidence for these agents is weak. They recommended exercise as treatment for fatigue together with HCQ but did not recommend either DHEA or anti-TNF inhibitors. They recommended rituximab for significant dry eye and mouth disease where other agents have failed and also recommended its use for systemic complications including cryoglobulinaemia, vasculitis, severe parotid swelling, inflammatory arthritis, pulmonary disease and peripheral neuropathy. Table 1 Summary of the scope of recent guidelines for the management of SS Author Region Methodology Eyes Mouth Systemic Patient input Zero et al., 2016 [4] North America Systematic review, Delphi consensus No Yes No Yes Foulks et al., 2015 [5] North America Systematic review, Delphi consensus Yes No No Yes Vivino et al., 2016 [6] North America Systematic review, Delphi consensus Yes Yes Yes Yes Sumida et al., 2018 [8] Japan Systematic review, Delphi consensus Yes Yes Yes No Carsons et al., 2017 [7] North America Systematic review, Delphi consensus No No Yes Yes Price et al., 2017 [10] Europe (UK) Systematic review, Delphi consensus Yes Yes Yes Yes Saraux et al., 2016 [9] Europe (France) Review Yes Yes Yes No Author Region Methodology Eyes Mouth Systemic Patient input Zero et al., 2016 [4] North America Systematic review, Delphi consensus No Yes No Yes Foulks et al., 2015 [5] North America Systematic review, Delphi consensus Yes No No Yes Vivino et al., 2016 [6] North America Systematic review, Delphi consensus Yes Yes Yes Yes Sumida et al., 2018 [8] Japan Systematic review, Delphi consensus Yes Yes Yes No Carsons et al., 2017 [7] North America Systematic review, Delphi consensus No No Yes Yes Price et al., 2017 [10] Europe (UK) Systematic review, Delphi consensus Yes Yes Yes Yes Saraux et al., 2016 [9] Europe (France) Review Yes Yes Yes No Table 1 Summary of the scope of recent guidelines for the management of SS Author Region Methodology Eyes Mouth Systemic Patient input Zero et al., 2016 [4] North America Systematic review, Delphi consensus No Yes No Yes Foulks et al., 2015 [5] North America Systematic review, Delphi consensus Yes No No Yes Vivino et al., 2016 [6] North America Systematic review, Delphi consensus Yes Yes Yes Yes Sumida et al., 2018 [8] Japan Systematic review, Delphi consensus Yes Yes Yes No Carsons et al., 2017 [7] North America Systematic review, Delphi consensus No No Yes Yes Price et al., 2017 [10] Europe (UK) Systematic review, Delphi consensus Yes Yes Yes Yes Saraux et al., 2016 [9] Europe (France) Review Yes Yes Yes No Author Region Methodology Eyes Mouth Systemic Patient input Zero et al., 2016 [4] North America Systematic review, Delphi consensus No Yes No Yes Foulks et al., 2015 [5] North America Systematic review, Delphi consensus Yes No No Yes Vivino et al., 2016 [6] North America Systematic review, Delphi consensus Yes Yes Yes Yes Sumida et al., 2018 [8] Japan Systematic review, Delphi consensus Yes Yes Yes No Carsons et al., 2017 [7] North America Systematic review, Delphi consensus No No Yes Yes Price et al., 2017 [10] Europe (UK) Systematic review, Delphi consensus Yes Yes Yes Yes Saraux et al., 2016 [9] Europe (France) Review Yes Yes Yes No Vivino et al. [6] authored a summary guideline that covered oral, ocular and systemic disease management. In line with the other guidelines, they recommended topical fluoride, stimulation of salivary flow, topical chlorhexidene and non-fluoride remineralization agents as adjunctive therapies for oral symptoms and prevention of caries. Their recommendations for dry eye disease were identical to those outlined by Foulks et al. and their recommendations for joint disease, fatigue and systemic symptoms mirrored those of Carsons et al. [7]. None of these guidelines considered paediatric onset disease or covered pregnancy or lymphoma management. Sumida et al. [8] aimed to develop a Clinical Practice Guideline to enhance diagnosis, help in evaluation of disease activity, and facilitate provision of early and effective treatment of SS in Japan. They formed a health professional committee with rheumatologists, ophthalmologists, dental and oral surgeons, and one each of an otolaryngologist, paediatrician and public health scholar, and undertook a systematic review followed by a Delphi process to reach a consensus. They made 38 recommendations. Seventeen recommendations dealt with diagnosis and prognosis, two with lymphoma, four with paediatric disease and the remaining 15 with patient management and treatment. They included the management of children and pregnant women and touched on the risk factors for lymphoma development. In line with other published guidelines, they recommended pilocarpine and cevimeline as oral secretagogues, topical moisturising agents for eyes and punctal plugs to preserve tears. They found no strong evidence supporting the use of systemic corticosteroids and immunsuppressive agents for glandular disease and were cautious about the benefits for systemic disease. In contrast to the North American and European guidelines, they did not recommend HCQ or MTX for patients with SS. They found conflicting evidence on the use of biologics but felt they may have a role in severe extra-glandular disease. They recommended a multi-disciplinary approach to the management of pregnancy in women with SS [8]. Saraux et al. [9] reviewed the available evidence on topical and systemic treatment for SS and recommended that treatment decisions should be based on the initial evaluation of symptoms and extraglandular manifestations; sicca should be managed with education, environmental modification and topical treatments; and corticosteroids and immunosuppressive agents should be considered for systemic manifestations. They felt that current evidence for biologic therapies was conflicting and that patients should be offered participation in ongoing randomized controlled trials wherever possible. In the UK, a recently published BSR NICE-approved guideline covers the management of oral, ocular and systemic disease in SS in detail [10]. The current article has been informed by evidence from this BSR guideline, from the systematic reviews discussed above, our personal experience and the ever-expanding literature. Unmet needs in Sjögren’s syndrome Available treatments for SS are often sub-optimal in terms of efficacy, creating significant unmet need. A panel of international experts addressed this and produced a working document to guide future research and development [11]. The panel concluded that the new ACR-EULAR classification criteria [12] should represent the gold standard for classification of patients entering studies; that the EULAR Sjögren’s syndrome disease activity index (ESSDAI) provides a reliable measure of systemic involvement and prognosis in SS; that data on both the ESSDAI and EULAR Sjogren’s syndrome patient reported index (ESSPRI) should be collected because of the poor correlation between them; that salivary gland biopsy and measurement of salivary flow should be included in clinical trials; and that current clinical, haematological and histological features are insufficient as bio-markers of SS. With respect to therapy, they recognized that current DMARD use was based on non-controlled studies and expert opinion, but nevertheless concluded that HCQ and MTX were effective for arthritis; cyclophosphamide was effective for severe vasculitis; and low dose corticosteroids in short courses were effective for constitutional symptoms, parotid enlargement and arthritis. They also concluded that biologics may represent effective treatment for SS in the future but larger, multicentre studies were needed to confirm this. General advice Humidification of air is a simple intervention that increases tear-film stability [13], reduces tear evaporation and improves dryness symptoms in general [14]. Sicca symptoms can be exacerbated by certain drugs, e.g. anti-cholinergics such as anti-depressants, anxiolytics and anti-psychotics; muscarinic antagonists such as tamsulosin hydrochloride and ipratropium hydrochloride; anti-histamines; opiates; anti-hypertensives including beta-blockers and angiotensin converting enzyme (ACE) inhibitors; and proton pump inhibitors such as omeprazole. Avoiding these entirely may not be practicable but use should be minimized if possible. There is some evidence supporting dietary supplementation with omega-3 fatty acids, with improvement in both Schirmer’s test and ocular inflammation in two studies of patients with symptomatic dry eye [15, 16], but a recent large multicentre, double blind clinical trial did not show significantly better outcomes in ocular symptoms or signs between those receiving 3000 mg of n − 3 fatty acids and those receiving placebo [17]. Nonetheless the North American and European guidelines recommend omega-3 supplementation [5, 6, 10]. There is low quality evidence supporting omega-7 supplementation [18]. Studies suggest that patients with SS benefit from moderate- to high-intensity exercise and cognitive therapies, such as mindfulness [19, 20]. Many patients report benefit from joining a support group. The British Sjögren’s Syndrome Association (BSSA) in the UK and the Sjögren’s Syndrome Foundation (SSF) in the USA provide information and advice for members via their websites, telephone helplines and quarterly magazines. The International Sjögren’s Network (ISN) links 15 global organizations, including patient support groups, and brings together researchers, clinicians and patients (https://www.sjogrens.org/home/get-connected/isn). Within the UK, Versus Arthritis (www.arthritisresearchuk.org) provides helpful information and leaflets on SS, anti-rheumatic drugs and life-style advice. Children and young adults SS in children and young adults is rare and usually presents with recurrent parotid swelling. The general management in this group is similar to that for adults with special emphasis on the importance of good dental care and hygiene to preserve dental health. Only the Japanese guidelines [8] specifically refer to paediatric patients with SS. The authors of the guidelines concluded that recurrent parotid swelling was the most common presenting symptom, affecting 60% of the paediatric cohort, while dryness or sicca was uncommon. They noted the presence of extra-glandular symptoms and signs and the high sensitivity of anti-Ro antibodies, sialography and labial salivary gland biopsy for diagnosis. Management of eye symptoms in Sjögren’s syndrome All patients with SS should ideally be under the routine care of an eye care professional, since assessment of ocular complications of this disease requires slit lamp examination and other forms of specialized testing. Those patients managed with HCQ also require annual monitoring for potential retinal toxicity. Dry eyes may be classified as mild, moderate or severe based on assessments of both symptoms and signs [21]. The majority of patients with SS will have severe dry eye (Schirmer’s ≤5 mm in 5 min and tear break-up time ≤5 s). In SS-associated dry eye, all three layers of the tear film may be affected with disruption to the mucus, aqueous and lipid layers, and each of these requires specific management. The mucosal surface depends upon a healthy surface epithelium. The commonly used preservatives in eye drops are toxic to the surface epithelium and ‘blunt’ the surface microvilli [22], reducing the effective surface area and disrupting the mucus-producing goblet cells. Preservative-containing eye drops or gels should thus be avoided in patients using eye drops long term (for >3 months) or more than four times daily (effectively the majority of patients with primary SS). Preservative-free preparations are now widely available, both in multi-dose bottles and single-use vials. The surface lipid layer produced by the meibomian glands within the eyelids prevents tear evaporation and its genesis can be stimulated by a microwaveable warm compress [23] for 7–10 min daily. When the meibomian gland ducts are blocked by scale or encrusted secretions, flow can be improved by cleaning the edges of the eyelids with a cotton-tipped bud and either a proprietary product or a weak solution of bicarbonate. Antibiotics may be required for some patients with persistent blepharitis and meibomian gland disease [24], e.g. doxycycline 50 mg od for 3 months or topical azithromycin ophthalmic solution 1% (twice daily for 2 days and once daily thereafter for 28 days) [25, 26]. Liposomal sprays (widely available over-the-counter but not currently FP10 prescribable in the UK) reduce evaporative tear loss and replace the meibomian gland layer and have been shown to significantly reduce sicca symptoms [27]. Moisture chamber glasses or spectacles can reduce surface evaporation of tears by up to 30%. Patients should be encouraged to avoid prolonged screen use, which reduces blink rate and encourages tear evaporation [28, 29]. Smoking has also been linked to dry eye disease and should be actively discouraged [30]. Punctal plugs [31, 32] retain aqueous tears within the eye and can improve symptoms of dry eye more than artificial tears alone. First line treatment should be with temporary plugs. If this is effective and tolerated then permanent punctal occlusion can be achieved with punctal cautery. To replace the aqueous tear film, we recommend preservative-free lubricating drops a minimum of four times daily. We also recommend using a higher viscosity, longer acting paraffin based preparation overnight or a carbomer gel if this is not tolerated. None of the commercially available tear supplements is clearly superior but, as a general principle, the thicker preparations are longer lasting but more likely to blur vision. Choice of preparation will depend on local availability, cost and patient preference. Sodium hyaluronate is not available as the active ingredient in tear supplements marketed in the USA, in contrast to many tear products marketed elsewhere. However, it is included as an inactive ingredient in a few products in the USA, although the concentration is not specified. If tear supplements with sodium hyaluronate are available, we recommend starting with a preparation containing a low concentration (0.1%) and increasing to a higher concentration (0.2–0.4%) if indicated. If this is not tolerated or sufficient, alternatives include carbomers, which may have better retention within the eye, polyvinyl alcohol-containing drops, which can stabilize the tear film, or combination products containing phospholipids. The North American and European guidelines list available preparations in online appendices [5, 10]. Autologous or allogeneic serum eye drops are expensive and only available in tertiary centres in Europe and from commissioned specialist centres in the UK following specialist ophthalmic review but can be very effective and are well tolerated by patients [34–35]. In the USA, autologous serum tears are available through specific compounding pharmacies. If there is ongoing corneal inflammation, low-dose corticosteroid-containing eye drops are safe and effective for short-term use [36] but this should ideally be supervised by an ophthalmologist [37]. For long-term use, ciclosporin- and lifitegrast-containing eye drops have been shown to be effective but must be prescribed by ophthalmologists in the UK [38–40]. A 0.1% ciclosporin preparation (Ikervis®) is licensed and NICE approved in the UK and available in Europe and a 0.5% preparation (Restasis) is licensed and available in the USA. An unlicensed veterinary ointment (Optimmune®, ciclosporin 0.2%) may be used as an alternative. Lifitegrast ophthalmic drops (Xiidra®) are available in the USA, but have not yet been approved for use in Europe. Topical NSAIDs such as diclofenac and indomethacin improve symptoms but reduce corneal sensitivity and may predispose to further corneal damage and should therefore be avoided in patients with SS [41, 42]. Mucolytic eye drops (e.g. acetylcysteine 5–10% non-preserved) are useful for patients with mucous threads or ocular surface filaments [43] and have also been shown to improve tear break-up time and Schirmer’s tests in patients with meibomian gland disease [44] Some patients with severe dry eye develop blepharospasm, and there are small case series describing a good response to botulinum toxin injections [45, 46]. For severe dry eye with surface damage, rigid, gas-permeable scleral contact lenses, which vault over the corneal surface and rest on the sclera, may protect the surface and create an optimized environment for healing [47–49]. Corneal grafting or amniotic membrane overlay may occasionally be required for significant corneal ulceration and corneal melt [50]. These are only available in specialist centres for severe corneal disease refractory to all other treatments. Management of dry mouth in Sjögren’s syndrome SS causes reduced salivary flow and increased viscosity of saliva due to relative deficiency of the aqueous component. Patients with resultant dry mouth may develop difficulty swallowing and talking, and increased dental decay, gum disease and tooth loss [51, 52]. They tolerate dentures poorly and often complain of sore, ulcerated gums as a consequence of rubbing. Halitosis and recurrent infections, including parotitis, intraoral candidiasis and angular cheilitis, may result. We advise that patients practice excellent oral hygiene, avoid sweetened and/or acidic food and beverages, and limit themselves to plain water between meals and from 1 h before bedtime and all through the night [4]. Assessment by an oral medicine specialist and/or regular visits to a general dental practitioner are recommended with the emphasis on preventive dental care. Patients should be advised to brush their teeth for a minimum of 2 minutes without rinsing at least twice daily (but not immediately after eating) including before bed using a pea-sized amount of high fluoride toothpaste (>1000 ppm) [4]. They also benefit from the use of interdental brushes. Chlorhexidine is available as an alcohol-free mouth wash that inhibits plaque formation on teeth and is useful for controlling gum disease [53]. It can be used twice daily for a maximum of 2 weeks every 3 months as prophylaxis against gum disease but overuse can lead to staining of teeth. Saliva substitutes provide symptomatic and short-lived relief of oral dryness and are widely available, although many patients prefer to sip water or suck ice cubes. We recommend preparations that are sugar-free with neutral pH and contain fluoride and other electrolytes, mimicking the composition of natural saliva. Chewing sugar-free gum increases saliva production and there is some evidence that xylitol may have a role in caries prevention in addition to its value as a non-sugar sweetener [54–56]. Systemic stimulation Oral muscarinic agonists (pilocarpine and cevimeline) can produce a useful increase in secretions in up to 70% of patients although side effects, including flushing, headache and sweating, may limit their use in some. Randomized, controlled trials of pilocarpine in patients with SS confirm significant symptomatic improvement, objective evidence of increased salivary flow [57–59], reduced levels of oral candida colonization [60], improved ocular dryness and tear film break-up time and increased goblet cell density in the surface of the eye, thus improving the mucous layer [61–65]. Our recommended starting dose of pilocarpine is 2.5 or 5 mg once daily, escalating at weekly intervals as tolerated to 5 mg qds (with meals and at bedtime). Contra-indications include uncontrolled asthma or cardiorenal disease, chronic obstructive pulmonary disease and acute iritis. Side effects are common and dose-dependent. They include sweating, palpitations, dyspepsia, diarrhoea, abdominal pain, flushing and increased urinary frequency. An observational study suggests that it is safe and effective in children as young as 9 years of age [66]. In patients with intolerable side effects, a smaller dose of drug can be tried, facilitated by the application of topical ocular pilocarpine drops to the oral cavity. The Palliative drug formulary suggests two to three drops of pilocarpine 4% eye drops (equivalent to 4–6 mg oral pilocarpine) as an off-licence use [67]. Cevimeline is an alternative, longer acting muscarinic agonist available in the USA and Japan but not Europe. It has a longer half-life and receptor occupancy time than pilocarpine with higher affinity for muscarinic receptors located on lacrimal and salivary gland epithelium. It causes less flushing but more gastrointestinal side effects than pilocarpine [68–70]. Treatment of oral candidiasis Oral candidiasis is a frequent problem in patients with SS-associated dry mouth [71] who often have high levels of candida carriage despite good dental hygiene [72]. The presence of dentures aggravates the problem, creating an environment particularly conducive to candidal persistence or re-infection. Patients may have visible white plaques (simple infection) or erythematous infection, which presents with a red, raw tongue or oral cavity. Effective treatment of the erythematous infection can alleviate oral burning and glossitis. Clinical experience suggests that whereas topical agents such as nystatin may be adequate to treat simple infection, oral fluconazole is required to treat erythematous infection. Angular cheilitis may be another manifestation of candidal infection in SS. It can be effectively treated with ketoconazole or miconazole cream topically for 2 weeks, using a clean cotton bud to apply to each side to prevent cross-contamination and persistence of infection [73]. In the USA, nystatin suspension and clotrimazole troches and lozenges are heavily sugared and oral fluconazole is thus the preferred treatment, particularly if anti-fungal treatment is required on a monthly basis to prevent recurrence of the oral candidiasis. Miconazole is available in the USA as a sugar-free buccal tablet for topical treatment of oral candidiasis and may be a suitable alternative, particularly if poor saliva flow results in ineffective delivery of systemically administered fluconazole to the oral cavity. Management of salivary gland enlargement Recurrent or persistent salivary gland enlargement may occur during disease ‘flares’ or may reflect duct obstruction due to strictures, stones or inspissated secretions. Our preferred investigation for enlarged salivary glands is ultrasound because it is non-invasive, well tolerated by patients and easily repeatable. Ultrasound may reveal active inflammation, infection, stones or adenomas [74]. Suspicious nodules can be evaluated with ultrasound-guided fine needle aspiration and core needle biopsy, obtaining material suitable for flow cytometry, cytology and histopathology. If there is acute inflammation in the absence of infection and stones, then a short course of oral prednisolone/prednisone or an intra-muscular injection of methylprednisolone acetate (Depo-Medrone® or Depo Medrol®) typically 120mg will often settle the glandular swelling promptly. There is anecdotal evidence that massaging the glands daily can prevent the formation of mucus plugs in glands affected by recurrent swelling. Some patients with recurrent parotid gland swelling may benefit from sialoendoscopy with saline irrigation of Stensen’s duct [75]. The development of a mass lesion in one salivary gland or persistent diffuse salivary gland enlargement should raise concern for the presence of lymphoma. Initial assessment may include ultrasonography with fine needle aspiration and core needle biopsy for flow cytometric, cytological, and histopathological analyses. In some cases, an excisional biopsy may be needed to obtain pathological material suitable for histopathological analysis. Systemic dryness A chronic dry cough is common and usually due to drying of mucosal surfaces. Humidification of inspired air may help, along with pilocarpine [14]. We have also occasionally used a mucolytic agent (i.e. carbocysteine or acetylcysteine) to reduce the viscosity of sputum and improve cough [76]. Chronic dry persistent cough may be a sign of interstitial lung disease and should prompt appropriate investigations. Women with SS frequently report uncomfortable vaginal dryness [77] and may have associated atrophy of the genital skin [78]. There is good evidence supporting the use of pH-balanced (acidic) non-hormonal moisturisers in the treatment of vaginal dryness from any cause [79–81]. We usually recommend combination with topical oestrogen creams or pessaries in post-menopausal patients, which, in addition to improving the quality of the genital tissues, can reduce the frequency of urinary tract infections [79]. Although systemic absorption can occur with local preparations, there is no current evidence of an increased risk of endometrial thickening [79]. Treatment of systemic disease Systemic (extra-glandular) features are seen in up to 70% of patients with SS and are severe in about 15% [82]. The most commonly involved organs are joints, lungs, skin and peripheral nerves [3]. Raynaud’s and thyroid disease tend to be commoner in females, and lung involvement and peripheral neuropathies are commoner in those with disease duration of >10 years [2]. Other systemic features may include autoimmune liver disease, renal involvement, SCLE, immune thrombocytopaenia, myositis, monoclonal gammopathy of uncertain significance and lymphoma. There are also common overlapping conditions, most notably thyroid disease in up to 20% [83], primary biliary cholangitis in 8% [84] and coeliac disease in 4.5% [85]. Immunomodulation for systemic disease Corticosteroids Corticosteroids (e.g. prednisolone and prednisone) have been shown to help systemic features including lung disease [86–88] cytopaenias [89], and, in combination with cyclophosphamide, neurological involvement [90, 91]. Small studies of low dose prednisolone (5–7.5 mg per day) have shown improvements in sicca symptoms and modest improvements in salivary flow [92]. The North American and European guidelines recommend short-term corticosteroid use if required but in general urge the use of steroid-sparing agents if use continues [6, 7, 10]. Our own practice is to limit steroid use to a short term in those with systemic complications. Hydroxychloroquine A number of studies [93–97] suggest modest improvements in ocular and oral dryness, lowering of ESR and immunoglobulin levels, together with reductions in fatigue levels and joint pain in patients treated with HCQ. The North American and European (but not the Japanese) guidelines recommend HCQ for arthralgia, arthritis [6, 7, 9, 10] and fatigue [6, 7, 10]. Our practice is to offer HCQ to patients with significant fatigue and joint pain although we acknowledge that the evidence base for this is not strong. Methotrexate MTX is considered the drug of choice for patients with significant inflammatory arthritis [98]. An open label, pilot study of weekly MTX in 17 patients showed improvement in sicca symptoms, parotid swelling, dry cough and purpura, but no improvement in objective parameters of dry eyes and mouth [99]. Despite the lack of clear evidence of efficacy and paucity of trial data, the European and North American guidelines all recommend the use of MTX in patients with SS-associated joint disease [6, 7, 9, 10]. Azathioprine Azathioprine has been reported as helpful in case reports for systemic complications such as lung disease [100], myelopathy [101] and cytopaenias [102] but a randomized controlled trial suggested that it did not have a routine role in treatment and was associated with a high frequency of side effects [103]. The Japanese guideline [8] did not recommend azathioprine and other guidelines suggest it only when other treatment strategies have failed or where a steroid-sparing effect is required. Our practice is to use it occasionally in patients with systemic complications such as lung and neurological disease. Mycophenolate A single-centre, open-label trial reported a significant reduction in hypergammaglobulinaemia and an increase in complement levels, but little effect on glandular features [104]. Case reports [105] support the use of mycophenolate in SS-associated agranulocytosis and interstitial lung disease [106, 107]. It is not recommended in the Japanese [8] or the North American guidelines [6, 7] but Saraux et al. [9] suggest considering it for lung disease, although concede this is based on empirical evidence alone. In practice, we have found it helpful and better tolerated than azathioprine in those with lung disease. Ciclosporin A There are anecdotal reports of successful treatment of SS-associated interstitial cystitis [108], annular erythema [109, 110], red cell aplasia [111] and pneumonitis [112] with oral ciclosporin. An open-label phase II study of low dose ciclosporin A (2 mg/kg) showed reductions in joint swelling and tenderness [113]. The Japanese guidelines do not recommend it [8] and the North American guidelines found scant evidence for its use [6]. In practice, we have found it poorly tolerated and rarely helpful in the longer term. Cyclophosphamide There are no controlled trials of cyclophosphamide in SS and in general its potential toxicity would preclude routine use. However there are published case reports and series documenting successful treatment of SS-associated myelopathy [90, 114], refractory thrombocytopaenia [115], glomerulonephritis [116, 117] and lung disease [118]. In practice, its use is reserved for those with progressive organ-threatening disease and in many of these clinical situations, rituximab would now be the treatment of choice across North America and Europe. The Japanese guidelines suggests its use in those with lung, kidney or CNS involvement [8]. Biologics for systemic disease Rituximab Rituximab has evidence of efficacy from small case series and case reports in the treatment of SS-related lymphoma, immune thrombocytopaenia, cryoglobulinaemia, membranoproliferative glomerulonephritis and neurological disease [119–129]. However, neither of the two phase III placebo-controlled trials reached their primary end point [130, 131] evaluating patient-reported improvements in pain, fatigue and dryness. Rituximab and other B cell-depleting therapies are currently the subject of multicentre trials but at present the UK-based guideline group [10] felt there was insufficient evidence to recommend routine use of rituximab in those with predominantly fatigue and sicca manifestations but good evidence for its use in systemic complications and lymphoma. Use of rituximab in primary SS is not currently NICE UK-approved and is not routinely funded for the treatment of SS in the UK with the exception of those patients presenting with lymphoma. The Japanese guideline group felt that rituximab and other biologics showed promise but urged caution in their use because of concerns over adverse effects including infections [8]. The North American guideline group felt that there was sufficient evidence to support rituximab in those patients for whom conventional therapies, including immunomodulators, had proven insufficient and particularly recommended it for those with vasculitis, severe parotid swelling, inflammatory arthritis, pulmonary disease and peripheral neuropathy [6, 7]. Saraux et al. [9] acknowledged the evidence for rituximab was not strong and advised that it be reserved for those with severe disease where other treatment options had failed or were inappropriate. Belimumab A small open-label study demonstrated a significant improvement in the ESSDAI score from baseline with particular improvement in non-malignant glandular swelling [132]. Although not currently routinely used in SS, belimumab has also been reported to be of benefit in combination with rituximab [133] and further trials of belimumab, including a combined study with rituximab, are currently underway. Abatacept Abatacept was well tolerated in one open label pilot study and fatigue and health-related quality of life improved significantly over a 24-week treatment period [134]. There are two phase III studies currently underway investigating abatacept in SS. (https://clinicaltrials.gov/ct2/show/NCT02067910 and https://clinicaltrials.gov/ct2/show/NCT03411850). Anti-TNF therapy Initial open-label studies of anti-TNF agents suggested some benefit [135–137] but subsequent randomized double-blind controlled trials failed to show clinical or serological improvement in patients with SS following treatment with etanercept [138] or infliximab [139]. None of the recently published guidelines recommend anti-TNF agents in primary SS although they comment that patients with RA or another CTD can safely receive anti-TNF if indicated [6, 7]. Other biologic agents A number of other biologic agents are in phase II and/or III studies for SS including tociluzimab, some novel agents and a number of Janus kinase inhibitors with details available on the clinical trials database (https://clinicaltrials.gov). Intravenous immunoglobulins There is evidence supporting the use of intravenous immunoglobulin therapy in SS-associated sensorimotor and non-ataxic sensory neuropathy from retrospective and observational cohorts and case reports [140, 141]. Immunoglobulin treatment has also been used successfully in refractory SS-associated myositis not responding to conventional treatment [142]. There is no evidence for its routine use in patients without significant systemic disease. Colchicine There are case reports describing successful treatment of SS-associated hypergammaglobulinaemic purpura [143], granulomatous panniculitis [144] and pericarditis [145] with colchicine. In our personal experience, it is helpful in patients with persistent pericarditis. Management of pregnancy Fertility is normal in patients with primary SS although there is an increased risk of recurrent miscarriage in the Ro/La+ group [146–148]. Neonatal lupus rash occurs in about 5% of live births in Ro/La positive women, usually appearing at 6 weeks of age and lasting about 17 weeks before fading and clearing completely. A few children have persistent depigmentation or telangiectasia [149]. Congenital heart block occurs in <2% of pregnancies in women with anti-Ro or -La antibodies and may be detected by ultrasound scanning from about 16 weeks’ gestation [150]. There is evidence that in anti-Ro positive women, fetal atrioventricular time intervals are longer and heart rates slightly lower compared with controls. Fetuses with normal atrioventricular time intervals at 18–24 weeks had normal electrocardiographic results at birth. Hence serial Doppler echocardiographic measurement of atrioventricular time intervals is suggested as a useful method for surveillance of these high-risk pregnancies [151]. Following an affected pregnancy the risk of congenital heart block goes up to 17% for subsequent pregnancies; 70% of affected children survive but nearly all require pacemakers in the first few months of life [152]. There is some evidence from longitudinal, observational studies that primary SS mothers deliver significantly earlier, give birth to babies with lower birth weight and have complications during deliveries more frequently than women in the general population [148]. Other, very rare, complications include hepatitis and cytopaenias affecting the newborn. Only a handful of cases have been reported in the literature and in the majority of cases the child has improved spontaneously [153]. Successful pregnancies are, however, increasingly common in patients with SS. There is evidence that low-dose aspirin initiated in early pregnancy improves placental implantation and reduces the incidence of both pre-eclampsia and intra-uterine growth retardation [154, 155]. It is safe to continue HCQ throughout pregnancy with evidence in patients with systemic lupus erythematosus of improved outcomes for the mother and no detrimental effects on the child [156–159]. The Japanese guidelines [8] recommend that a multi-disciplinary team manages pregnancy in women with SS and we would concur with this approach. Assessment of lymphoma risk The risk of lymphoma development in patients with primary SS increases from 3% in the first 5 years to 9.8% at 15 years, i.e. up to 40 times the population risk [160–162]. The presence of lymphadenopathy, persistent parotid enlargement, palpable purpura, low serum C4 levels and cryoglobulins are the most consistent predictors of future risk [163] and may increase the risk of future development of lymphoma up to 5-fold [161]. The detection of germinal centre-like structures or a focus score ≥3 on light microscopy in diagnostic salivary gland biopsies from patients with primary SS may suggest a future higher risk for lymphoma development [164]. The majority are marginal zone lymphomas of the Mucosa-associated lymphoid tissue type. The median age of onset is mid-50 s and the diagnosis of SS generally pre-dates the lymphoma by a mean of 7 years [160]. Commonest sites of presentation include the parotid and other salivary glands, followed by the orbits, stomach, thyroid, lung, upper airways and rarely other sites [165]. Presentation is usually with a firm, palpable swelling within the gland, although diffuse, symmetric glandular enlargement may also be seen. GI tract lymphoma may present with chronic diarrhoea, malabsorption and weight loss [166]. Management of mucosa-associated lymphoid tissue lymphoma Ultrasound allows assessment of any new swelling within the major salivary glands and, used in conjunction with Doppler signals, may help differentiate between benign and malignant lesions. [74]. Biopsy is usually necessary to confirm the diagnosis. CT or magnetic Resonance (MR) scanning of the head and neck defines the extent of salivary gland involvement and presence of regional lymph node involvement. Limited disease can be managed with a ‘watch and wait’ approach, particularly in the absence of active systemic disease that might require treatment of its own accord [125, 127]. Other treatments include rituximab monotherapy, low dose radiotherapy, or surgical excision if the lymphoma is confined to a single nodule. Disseminated disease generally requires rituximab administered with chemotherapy, such as bendamustine or the CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) regimen. The prognosis is generally good with a complete response to initial treatment in >90% and 5 year disease-free survival >75% [165], but splenomegaly, low serum C3, levels, neutropaenia and lymphopaenia may indicate a higher risk of poor outcome [163]. The Japanese guidelines [8] recommend careful assessment of salivary gland swelling and measurement of C3 and C4 levels in patients with SS to identify those at particular risk of lymphoma. 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TI - How to treat Sjögren’s syndrome
JF - Rheumatology
DO - 10.1093/rheumatology/key363
DA - 2019-02-15
UR - https://www.deepdyve.com/lp/oxford-university-press/how-to-treat-sj-gren-s-syndrome-cjAhdvCNIt
SP - 1
VL - Advance Article
IS - 
DP - DeepDyve
ER -