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14-07-2016 | Sjögren’s syndrome | Review | Article

Treatment of primary Sjögren syndrome

Journal:
Nature Reviews Rheumatology

Authors: Alain Saraux, Jacques-Olivier Pers, Valérie Devauchelle-Pensec

Publisher: Nature Publishing Group UK

Abstract

Primary Sjögren syndrome (pSS) is a progressive autoimmune disease characterized by sicca and systemic manifestations. In this Review, we summarize the available data on topical and systemic medications, according to clinical signs and disease activity, and we describe the ongoing studies using biologic drugs in the treatment of pSS. Expanding knowledge about the epidemiology, classification criteria, systemic activity scoring (ESSDAI) and patient-reported outcomes (ESSPRI) is driving active research. Treatment decisions are based on the evaluation of symptoms and extraglandular manifestations. Symptomatic treatment is usually appropriate, whereas systemic treatment is reserved for systemic manifestations. Sicca is managed by education, environment modification, elimination of contingent offending drugs, artificial tears, secretagogues and treatments for complications. Mild systemic signs such as fatigue are treated by exercise. Pain can require short-term moderate-dose glucocorticoid therapy and, in some cases, disease-modifying drugs. Severe and acute systemic manifestations indicate treatment with glucocorticoids and/or immunosuppressant drugs. The role for biologic agents is promising, but no double-blind randomized controlled trials (RCTs) proving the efficacy of these drugs are available. Targets for new treatments directed against the immunopathological mechanisms of pSS include epithelial cells, T cells, B-cell overactivity, the interferon signature, proinflammatory cytokines, ectopic germinal centre formation, chemokines involved in lymphoid cell homing, and epigenetic modifications.

Saraux A et al. Nat Rev Rheum 2016; 12: 456–471. doi: 10.1038/nrrheum.2016.100

Main

Sjögren syndrome is a progressive autoimmune disease. The hallmark manifestation of Sjögren syndrome is sicca, which is caused by lymphocytic infiltrates that eventually destroy the lachrymal and salivary gland tissue1. Parotid gland enlargement, although rare, is suggestive of Sjögren syndrome when bilateral or accompanied by other signs2.
Sjögren syndrome can also cause systemic manifestations, which mainly involve the musculoskeletal system, nervous system, lungs, kidneys, skin and blood vessels1,3. Severe quality-of-life impairments are seen consistently in patients with Sjögren syndrome, even in those patients who have no systemic manifestations. Primary SS (pSS) occurs alone, whereas secondary Sjögren syndrome occurs in combination with another autoimmune disorder. As a rule, secondary Sjögren syndrome is not very severe, and the accompanying disease is the main determinant of treatment decisions. Consequently, this Review focuses on pSS, although sicca is treated identically in both types of Sjögren syndrome.
At present, pSS is diagnosed using the 2002 ACR–EULAR criteria4 or 2012 ACR criteria5. The existence of two different criteria sets can raise difficulties, and an ACR–EULAR expert panel recently came to a consensus on a new criteria set. These new ACR–EULAR classification criteria, although still unpublished, were reported by Shiboski et al.6 at the International Symposium on Sjögren's Syndrome in Bergen in May 2015. They are intended to be used in patients with signs suggesting pSS, mainly sicca. Points are given based on the focus score , positive serology for antibodies to Sjögren syndrome-related antigen A (SSA; also known as Ro), ocular staining score (OSS) for one eye ≥5 (or van Bistjerveld score ≥4), Schirmer's test result ≤5 mm per 5 min and unstimulated whole salivary flow rate ≤0.1 ml per min. Nevertheless, when seeking to diagnose pSS, differential diagnosis is as important as identifying these disease criteria, which are classification and not diagnostic criteria2.
The EULAR task force on pSS has created two new tools for assessing disease activity and patient-reported outcomes. The EULAR Sjögren's syndrome disease activity index (ESSDAI)7 is the sum of scores for each organ-specific domain (constitutional, lymphadenopathy, glandular, articular, cutaneous, respiratory, renal, muscular, peripheral nervous system, central nervous system (CNS), haematological and biological) multiplied by the activity level (range 0–3). The minimal clinically significant difference for the ESSDAI is 3 points8. The EULAR Sjögren's syndrome patient-reported index (ESSPRI)9 combines visual analogue scales (VASs) for sicca, pain and fatigue. The minimal clinically significant difference is 1 point8.
The ESSDAI and ESSPRI are increasingly being used as inclusion criteria and endpoints in clinical trials evaluating therapies for pSS. Predictors of extraglandular manifestations of pSS, including lymphoma development, are also considered as inclusion criteria. The main known predictors of extraglandular manifestations are parotidomegaly, purpura, polyadenopathy, vasculitis, anaemia, lymphopenia, hypocomplementaemia (low serum levels of complement protein C4), cryoglobulinaemia, elevated serum levels of Fms-related tyrosine kinsase 3 ligand (FLT3L), presence of germinal centres within the salivary glands, and the His159Tyr mutation of the B-cell-activating factor receptor (BAFFR; also known as TNFRSF13C)10,11,12,13,14.
The objective of this Review is to summarize the available data on topical and systemic medications for pSS according to clinical signs and disease activity, and also to summarize previous and ongoing studies using biologic agents in pSS.

General principles of pSS treatment

Experts suggest that patients with Sjögren syndrome should be managed by a multidisciplinary team including at least a rheumatologist, a dentist and an ophthalmologist15. The few available systematic literature reviews16,17,18 have highlighted the paucity of rigorous clinical trials on which to base clear guidelines, which explains the current reliance on expert opinion15,16,17,18,19. Tables 1, 2 summarize the principles of the treatment of pSS and the grade of recommendation according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence (see Further information).
Table 1
Treatments for the manifestations of primary Sjögren syndrome and grade of recommendation*
Manifestations of pSS
Treatment and/or course of action
Dryness
Dry mouth
• Topical fluoride (A)
• Gustatory and masticatory stimulation (C)
• Pharmaceutical agents; chlorhexidine varnish, gel or rinse; electrostimulation (C)
• Secretagogues: pilocarpine and cevimeline (A)
• Education and environment modification; elimination of offending drugs (A)
Dry eyes
• Education and environment modification; elimination of offending drugs; artificial tears; gels and/or ointments (A)
• Local ciclosporin (B)
• Pulsed glucocorticoids (C)
• Punctal plugs (C)
• Secretagogues: pilocarpine and cevimeline (A)
Meiombian disease
• Artificial tears with lipid components; warm compress and massage; topical azithromycin; liposomal spray; oral doxycycline; excision of the meibomian glands; systemic anti-inflammatory medication; eyelid surgery (C)
Parotid enlargement
Acute bilateral severe parotid swelling
• Look for lymphoma
• If lymphoma excluded, treat with glucocorticoids (B)
Chronic bilateral parotid swelling
• Look for lymphoma
• Surgery required in rare cases (D)
Acute unilateral severe parotid swelling
• Look for infection (ultrasonography): if present, treat with appropriate antibiotics (D)
• Look for infection or calcification in the ducts
• If infection and calcification excluded, treat with glucocortioids <20 mg per day for <1 month) (D)
Extraglandular signs
Non-life-threatening signs
• Exercise for fatigue (C)
• NSAIDs for arthralgia or arthritis (C)
• Hydroxychloroquine for arthralgia, arthritis, fatigue or cutaneous signs (see Table 1) (C)
• Imunosuppressant drugs (e.g. leflunomide, sulfasalazine, azathioprine, ciclosporin, cyclophosphamide) and/or glucocorticoids should be considered according to disease activity (see Table 2)
Life-threatening signs
Pulsed methylprednisolone and plasma exchange if cryoglobulinaemia (C)
Co-occurrence of cryoglobulinaemia and vasculitis
Rituximab should be considered (C)
pSS, primary Sjögren syndrome.
*Letters in brackets indicate the grade of recommendation according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence (see Further information). Levels 1 to 5 are as follows: 1a, systematic review of randomized controlled trials; 1b, individual randomized controlled trial; 1c, all-or-none case series; 2a, systematic review of cohort studies; 2b, individual cohort study; 2c, 'outcomes' research; 3a, systematic review of case–control studies; 3b, individual case–control study; 4, case-series; 5, expert opinion. Grade A is assigned when there is consistent evidence from level 1 studies. Grade B is assigned when there is consistent evidence from level 2 or 3 studies, or when extrapolations can be made from level 1 studies. Grade C is assigned when there is consistent evidence from level 4 studies, or when extrapolations can be made from level 2 or 3 studies. Grade D is assigned when there is level 5 evidence or troublingly inconsistent or inconclusive studies of any level.
Table 2
Treatment of primary Sjögren syndrome according to the ESSDAI score by domain
Domain
ESSDAI score*
 
Low
Moderate
High
Constitutional
• Advise patients with fatigue to exercise (B)
• Hydroxychloroquine (C)
• Short-term oral glucocorticoids (C)
• NA
Lymphadenopathy
• Abstention (D)
• Abstention (D)
• Treatment as for lymphoma (D)
Glandular
• Abstention (D)
• Abstention (D)
• Short-term oral glucocorticoids (D)
• Sialendoscopy (D)
• Intraductal glucocorticoids (D)
Arthralgia or arthritis
• Treatment as for chronic pain, with NSAIDs (C)
• Hydroxychloroquine (C)
• Methotrexate (D)
• Short-term oral or intra-articular glucocorticoids if arthritis (C)
• Hydroxychloroquine (C)
• Methotrexate (D)
• Second-line DMARDs as for rheumatoid arthritis if arthritis (C)
• Oral glucocorticoids but as briefly as possible (D)
Cutaneous
• Abstention (D)
• Cutaneous topical agents (C)
• Abstention (D)
• Cutaneous topical agents (C)
• Hydroxychloroquine (C)
• Hydroxychloroquine (C)
• Oral glucocorticoids (C)
Respiratory
• Treatment of sicca, inhaled glucocorticoids or β2 adrenergic agonists (D)
• Careful monitoring or oral glucocorticoids (D)
• Oral or IV glucocorticoids, immunosuppressants, pirfenidone or nintedanib (C)
Renal
• Abstention and careful monitoring (D)
• Glomerular disease: glucocorticoids (D)
• Tubulopathy: K+ and HCO3 if necessary (D)
• Glomerular disease: glucocorticoids (C)
• Tubulopathy: K+ and HCO3 if necessary (D)
• Rituximab if cryoglobulinaemia (D)
Muscular
• Abstention (D)
• Glucocorticoids (D)
• Methotrexate plus glucocorticoids (D)
Peripheral nervous system
• Treatment as for chronic pain (D)
• Oral or IV glucocorticoids or IVIg or both (D)
• IV glucocorticoids or IVIg or immunosuppressants (D)
Central nervous system
• NA (D)
• Oral or IV glucocorticoids (D)
• Glucocorticoids or immunosuppressants (D)
*Letters in brackets indicate the grade of recommendation according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence (see Further information). Levels 1 to 5 are as follows: 1a, systematic review of randomized controlled trial; 1b, individual randomized controlled trial; 1c, all-or-none case series; 2a, systematic review of cohort studies; 2b, individual cohort study; 2c, 'outcomes' research; 3a, systematic review of case–control studies; 3b, individual case–control study; 4, case-series; 5, expert opinion). Grade A is assigned when there is consistent evidence from level 1 studies. Grade B is assigned when there is consistent evidence from level 2 or 3 studies, or when extrapolations can be made from level 1 studies. Grade C is assigned when there is consistent evidence from level 4 studies, or when extrapolations can be made from level 2 or 3 studies. Grade D is assigned when there is level 5 evidence or troublingly inconsistent or inconclusive studies of any level. DMARD, disease-modifying antirheumatic drug; ESSDAI, EULAR Sjögren's syndrome disease activity index; IV, intravenous; IVIg, IV immunoglobulins; NA, not applicable (high activity is not listed in the ESSDAI); NSAID, non-steroidal anti-inflammatory drug.
Conclusive evidence of efficacy exists only for pilocarpine and cevimeline to treat sicca, and topical ciclosporin to treat moderate or severe ocular dryness (Table 3). Few published randomized controlled trials (RCTs) have focused on extraglandular signs (Table 3).
Table 3
Randomized controlled trials of treatments for primary Sjögren syndrome
Drug
Inclusion criteria
n
Primary endpoint
Primary endpoint met?
Refs
Secretagogues and electrostimulation
Pilocarpine
1993 ACR criteria
44
Increased saliva production at weeks 6 and 12 and global improvement of dry mouth (VAS)
Yes
35
1993 ECCC criteria
373
Improvement of dry mouth and dry eyes (VAS) at weeks 6 and 12 and increased salivary flow
Yes
33
2002 AECG criteria
256
Improvement of dry mouth and dry eyes at week 12
Yes
34
2002 AECG criteria
85
Improvement of ocular symptoms at week 12
Yes
50
Cevimeline
2002 AECG criteria and associated lachrymal and salivary gland dysfunction
75
Improvement of dry mouth and dry eyes (VAS) at week 6
Yes
37
2002 AECG criteria
44
Improvement of dry mouth and whole salivary flow rate
Yes for dry mouth
38
Confirmed or suspected pSS based on the Japanese Ministry of Health and Welfare criteria
60
Improvement in subjective symptoms of dry eyes at week 4
Yes
172
2002 AECG criteria
197
Improvement of dry eyes, dry mouth, and overall dryness at weeks 3, 6, 9 and 12
Yes
36
Electrostimulation
Patients with xerostomia and focal chronic sialadenitis
29
Improvement in whole salivary flow rate at week 4
No
30
Patients with xerostomia, including 66 meeting 2002 AECG criteria
114
Improvement in xerostomia severity at week 12
Yes
32
Non-biologic systemic treatments
Hydroxychloroquine
2002 AECG criteria
120
30% improvement in two of three or all three VAS scores for dryness, pain and fatigue
No
54
Dehydroepiandrosterone
2002 AECG criteria and MFI-20 general fatigue score ≥14 and low serum level of dehydroepiandrosterone
107
Fatigue (MFI-20)
No
57
Females, 2002 AECG criteria and focus score≥1
60
Fatigue (MFI-20)
No
55
Omega 6
Copenhagen criteria or Vitali's preliminary criteria for pSS
90
Fatigue (VAS)
No
56
Azathioprine
2002 AECG criteria
25
Clinical and biological efficacy
No
173
Hydroxychloroquine
pSS
19
Clinical and biological efficacy
No, except on hypergammaglobulinaemia, IgM and ESR
58
Cyclosporine A
pSS with at least two of three features among dry eyes (Schirmer's test result ≤5 mm or positive slit lamp exam), xerostomia (stimulated whole salivary flow rate ≤1ml per min per gland) or history (or presence) of parotid gland enlargement
10
Clinical and biological efficacy
No, except subjective xerostomia
174
Biologic treatments
Etanercept
2002 AECG criteria, dryness and active pSS (ESR or IgG levels)
14
Two of three domains among dry mouth, dry eyes, and IgG level or ESR
No
60
Infliximab
2002 AECG criteria, and two of three VASs for joint pain, fatigue, and the most severe VAS for dryness reported by each individual patient >50 mm
103
Two of three VASs for joint pain, fatigue, and the most severe VAS for dryness reported by each individual patient
No
59
Rituximab
2002 AECG criteria and fatigue
17
>20% reduction in fatigue VAS
No (but some improvement in fatigue)
40
2002 AECG criteria, stimulated whole salivary flow rate ≥0.15 ml per min, autoantibodies and salivary gland biopsy grade III or IV
30
Stimulated whole salivary flow rate
Yes
39
2002 AECG criteria and recent disease with biological activity or systemic manifestations and VAS >50 mm for global disease, pain, fatigue and dryness
122
Two of four VASs (for global disease, pain, fatigue and dryness)
No (slight efficacy for fatigue and sicca)
41
2002 AECG criteria, fatigue, oral dryness, anti-SSA/Ro antibodies and unstimulated salivary flow rate >0 ml per min with systemic involvement if disease duration >10 years
110
Fatigue (VAS) or oral dryness score
No (slight efficacy for sicca)
Anakinra
2002 AECG criteria and fatigue
26
Fatigue (VAS)
No
175
AECG, American–European Consensus Group; ECCC European Study Group on Classification Criteria; ESR, erythrocyte sedimentation rate; MFI -20, 20-item Multiple Fatigue Inventory; pSS, primary Sjögren syndrome; VAS, visual analogue scale.

Topically treated manifestations

Dry mouth

Saliva has lubricating, buffering and antimicrobial effects, and thus inadequate saliva production (hyposialia) adversely affects oral health20,21. Patients with pSS can have difficulty swallowing dry foods, chewing and speaking, as a result of xerostomia (dry mouth). They are susceptible to multiple caries and oral infections such as candidiasis, and their oral mucosa can become friable22. Studies have, however, yielded conflicting results regarding the prevalence23,24 and severity25,26 of periodontal disease in patients with pSS compared with healthy controls. Nonetheless, patients with pSS must be educated about the need for regular oral-health monitoring and care to prevent periodontal disease. Preventive measures target the biofilm, cavity formation, periodontitis and oral candidiasis. The severity of hyposialia (mild, moderate or severe) must be carefully evaluated before muscarinic agonist therapy is considered.
In patients with mild hyposialia, the first-line treatment combines saliva substitutes, lubricating agents and mechanical stimulation by chewing sugar-free gum, as a potential for saliva-flow stimulation persists in this situation. As previously reported, the viscoelastic properties of different saliva substitutes should be tested to determine which is best for a particular patient27. There is no strong evidence that any topical treatment is effective in relieving symptoms of xerostomia16, but the use of topical fluoride to prevent caries is strongly recommended. Daily use of fluoride dentifrices and gels containing 1.1% sodium fluoride28 or at least weekly use of 0.2% neutral fluoride rinse, combined with 5% neutral fluoride varnish every 6 months, is recommended29. The first two studies evaluating mild intra-oral electrostimulation in 101 patients with Sjögren syndrome showed little effect on xerostomia30,31. However, in a multicentre RCT in 66 patients with pSS, electrostimulation alleviated the oral dryness and had no adverse effects32.
In patients with moderate-to-severe oral dryness but with residual salivary-gland function (demonstrated by measuring the stimulated whole salivary flow rate), oral muscarinic agonists such as pilocarpine or cevimeline are the treatment of choice in the absence of contraindications18. The oral doses that provide the best compromise between efficacy and adverse effects are 5 mg every 6 h for pilocarpine and 30 mg every 8 h for cevimeline, as demonstrated in RCTs33,34,35,36,37,38 (Table 3). Commonly reported systemic adverse effects include sweating, a sensation of warmth or flushing, increased urinary frequency, headache, nausea, sinusitis, diarrhoea, pharyngitis and abdominal pain.
Among biologics, only rituximab has been associated with an improvement of oral dryness and unstimulated whole salivary flow39,40,41 (Table 3). However, rituximab seems to only be effective for oral dryness in early disease or in patients with some residual salivary gland function39, and, on the basis of the benefit:risk ratio, rituximab use is debatable for this indication.

Dry eyes

Keratoconjunctivitis sicca, the main ocular manifestation of pSS, results from damage to the corneal and conjunctival epithelium that occurs secondary to accelerated tear-film break-up and changes in tear composition. The evaluation of ocular dryness (also known as xeropthalmia) usually relies on three features: tear function, tear composition and ocular surface alterations19. As with the management of xerostomia, the treatment of ocular dryness varies with the severity of the condition and the response to each treatment.
Preventive measures include environmental modifications, avoidance of systemic drugs that reduce tear production, and good eyelid-margin hygiene. These measures can alleviate mild and intermittent symptoms. When these measures are inadequately effective, the first-line treatment is the use of artificial tears at least twice daily42. Data on the impact of eye drops on the ocular surface support the use of preservative-free artificial tears containing hyaluronate or carboxymethylcellulose43,44,45. Lubricating ointments are usually reserved for administration at bedtime as they are long-lasting and they can impair vision18.
Given the presence of ocular surface inflammation in keratoconjunctivitis sicca, topical anti-inflammatory drugs can be useful in patients with moderate or severe ocular surface disease19. Their use should be as brief as possible to avoid adverse events associated with long-term exposure46. RCTs support the use of 0.05% or 0.1% topical ciclosporin twice daily for patients with moderate-to-severe ocular dryness, although no further benefits are observed beyond 6 months of treatment47,48,49. Pilocarpine and cevimeline, which are also used to stimulate salivary flow, have been found effective in reducing dry-eye symptoms and, in some studies, objective signs of dry eye33,36,50. Finally, for the most refractory cases, blockage of the tear drainage system by punctal occlusion increases the residence time of ocular surface tears or instilled artificial tears and decreases the signs and symptoms of keratoconjunctivitis sicca19.
In cases with meibomian gland dysfunction, other therapeutic approaches can be considered, including artificial tears with lipid components, warm compress and massage, topical azithromycin, liposomal spray, oral doxycycline, warming glasses and mask, thermal pulsed compression, manual expression of meibomian glands, systemic anti-inflammatory medication or eyelid surgery19.
Among RCTs of biologics in pSS, only one study (of rituximab) has reported an improvement of VAS score for ocular dryness39. Thus, there is currently insufficient evidence for the use of biologics for ocular dryness.

Systemically treated manifestations

Whereas sicca symptoms can be treated using topical medications, other manifestations of pSS require systemic treatment. In this section, we discuss systemic treatments for non-life-threatening manifestations according to clinical signs and disease activity. Life-threatening manifestations are discussed separately below.

Fatigue

Chronic fatigue and impaired mental well-being are debilitating manifestations of pSS that severely impair quality of life51. Fatigue is often reported in pSS and other autoimmune diseases, but it is not consistently present, and its severity and associated psychological profiles vary across patients52. The pathophysiology of fatigue is unknown5 but probably involves multiple factors.
Obstacles to the evaluation of fatigue in RCTs include the presence of many confounding factors (such as anxiety, depression, fibromyalgia, sicca and pain)53 and the high prevalence of fatigue in the general population. Furthermore, several instruments are available for assessing fatigue17, but they reflect different components of this symptom. Thus, fatigue is rarely chosen as the primary outcome in RCTs40,54,55,56,57, which could introduce bias into the interpretation of the results.
Several compounds have shown no efficacy in reducing fatigue in pSS RCTs. These include the essential omega-6 fatty acid gamma-linolenic acid56, dehydroepiandrosterone55,57 and hydroxychloroquine54,58. Of the biologics that have been evaluated in pSS, the TNF inhibitors etanercept and infliximab failed to improve fatigue in two RCTs59,60, and belimumab — a monoclonal antibody targeting B-cell-activating factor (BAFF; also known as TNFSF13B) — did not significantly improve fatigue in an open-label study in which fatigue was part of the composite primary endpoint61. By contrast, fatigue was improved in a small open-label study of the TNF inhibitor abatacept62. In terms of RCTs, only rituximab has shown some evidence of efficacy in one small study40 (although the primary endpoint was not met) and in the TEARS trial41. However, the large TRACTISS RCT showed no effect of rituximab on fatigue63,64.
In conclusion, evaluating fatigue and elucidating its pathophysiological underpinnings are persistent challenges. RCTs have not identified any treatments with efficacy for fatigue, the only possible exception being rituximab, the effects of which seem to be modest at best. However, the design of some studies (for example, the inclusion of a large number of centres that are not equipped to apply tools such as ESDDAI, or studies that apply the ESSDAI retrospectively) might have underestimated treatment efficacy in terms of fatigue and also other outcome parameters.

Glandular involvement

Enlargement of the salivary glands, predominantly the submandibular and parotid glands, is a hallmark of pSS. Salivary-gland enlargement can be associated with pain, disfigurement, or chronic suppurative sialadenitis with abscess formation due to mucus retention in the ducts2,65. Differential diagnoses in patients with symmetric salivary-gland enlargement are sarcoidosis, immunoglobulin G4 (IgG4) disease, lymphoma and anorexia. Unilateral gland enlargement requires investigations to rule out lymphoma and other salivary-gland tumours.
The current treatment strategy for salivary gland enlargement is based on clinical experience and not on data from RCTs. In patients with a definitive diagnosis of pSS and no abscesses, salivary gland enlargement is treated using NSAIDs or short-term glucocorticoid therapy.
The main causes of obstructive sialadenitis are sialolithiasis , which chiefly affects the submandibular glands, and chronic recurrent sialadenitis without sialolithiasis. Sialoendoscopy using minimally invasive techniques relieves the pain and swelling66,67,68 and can be combined with irrigation of the duct system, intraductal glucocorticoid injection, mechanical dilation or endoscopy-assisted surgical interventions (such as papillotomy, distal ductal incision, or marsupialization of the excretory duct into the oral cavity). Another treatment option is botulinum toxin type A injection. Surgical parotidectomy has been suggested to treat refractory painful swelling, but this procedure can induce transient or permanent facial nerve injury, postoperative pain and persistent inflammation of the residual parotid tissue69.
Several studies have evaluated the efficacy of biologics to treat salivary gland enlargement, but no such treatment has shown efficacy in RCTs; for example, data from small studies suggesting a beneficial effect of rituximab therapy were not confirmed in the TEARS trial41, and no double-blind studies for other biologics have been published. Open-label studies using belimumab70 and abatacept62 suggest an effect of these drugs on the salivary gland component of the ESSDAI, but this efficacy needs to be confirmed in RCTs.

Arthralgia and arthritis

Joint manifestations occur in nearly half of patients with pSS71, and they include chronic arthralgia (which equally affects the small and large joints), recurrent symmetrical arthralgia or arthritis, and peripheral small-joint synovitis mimicking rheumatoid arthritis72. These conditions are often associated with other systemic manifestations. When present, synovitis is mild and usually non-erosive72.
The main drugs used to treat arthralgia and arthritis are symptomatic agents (NSAIDs, hydroxychloroquine, methotrexate, leflunomide and glucocorticoids). Except for hydroxychloroquine, these treatments are used empirically to treat arthralgia and arthritis in pSS, on the basis of their efficacy in treating systemic lupus erythematosus (SLE) or rheumatoid arthritis.
Hydroxychloroquine is the 'disease-modifying' drug most widely used to treat arthalgia in pSS, and its use is based on retrospective and open-label studies suggesting benefits from a dose of 6–7 mg per kg per day73,74. Notably, two RCTs54,58 provided no conclusive evidence of efficacy on joint manifestations; however, the primary endpoint in both of these studies was sicca and not joint symptoms.
Methotrexate is the cornerstone of arthritis treatment in pSS, as it is in the treatment of SLE and rheumatoid arthritis. However, its efficacy in this indication is unproven, the optimal weekly dosage is unknown and its liver toxicity must be monitored. Leflunomide has a similar mechanism of action to methotrexate, which could explain its efficacy in treating pSS75. Low-dose glucocorticoid therapy is considered effective for controlling arthritis in pSS72; however, to avoid adverse effects, the treatment duration should be limited.

Cutaneous manifestations

Treatment of dry skin and pruritus in pSS is similar to the management of xerosis in other conditions, and so here we focus on other cutaneous manifestations, namely annular erythema and vasculitis.
Annular erythema (an equivalent of subacute cutaneous lupus erythematosus) affects 10% of patients with pSS76 and is characterized by an erythematous, photosensitive rash with a wide elevated border and central pallor (annular polycyclic lesions). These lesions clear without scarring or atrophy, but can result in hypopigmentation76. A diagnostic skin biopsy is not mandatory. The most common sites of involvement are the face, neck and upper limbs. Some cutaneous lesions that are considered as annular erythema are associated with the presence of anti-SSA/Ro and/or anti-SSB/La antibodies76.
Topical treatment is the first-line strategy for annular erythema, and systemic treatments can be used subsequently. Topical glucocorticoids are the mainstay of the treatment, although their efficacy in cutaneous lupus has been confirmed in only one RCT77. The glucocorticoid class is selected on the basis of the location and activity of the skin lesions78. Systemic treatment might be indicated in patients with extensive or unsightly lesions.
Few RCTs are available, and no new systemic treatments have been developed for the cutaneous manifestations of pSS. On the basis of a single RCT, patients receive hydroxychloroquine or chloroquine as the first-line systemic drug79. The serum chloroquine concentration can be helpful to adjust the drug dose to optimize the clinical response. Patients should be advised not to smoke as tobacco could minimize the therapeutic effects of hydroxychloroquine and chloroquine80. Extrapolating from a non-randomized, non-contolled study reporting the efficacy of methotrexate in patients with SLE and annular erythema78, methotrexate is used as a second-line remission-inducing drug in patients with pSS who have annular erythema. Systemic glucocorticoids, azathioprine, dapsone, thalidomide and mycophenolate mofetil are other treatment options for patients with refractory forms of annular erythema.
Vasculitis is reported to be a feature in ∼10% of pSS cases, and purpura is the most common lesion1,81. The vast array of other vasculitic skin manifestations includes ulcers, gangrene, pitting scars, micro-infarcts, urticarial lesions, petechiae (diffuse purpura), peri-ungual infarction, non-tender erythematous lesions, and nodules. The treatment of cutaneous vasculitis can be complicated by the concomitant presence of visceral vasculitis, which carries a more severe prognosis. Systemic glucocorticoids are the most widely used drugs, although azathioprine, mycophenolate mofetil and methotrexate might deserve consideration80.

Pulmonary involvement

Pulmonary involvement can occur in all connective tissue diseases, and it is present in 10–20% of patients with pSS81,82. The lung interstitium is predominantly affected, and bronchiolitis and bronchiectasis are common83. The severity of lung disease is evaluated on the basis of dyspnoea, chest radiography, thin-section high-resolution CT, lung function testing, a test of the diffusing capacity of the lung for carbon monoxide (DLCO), and the 6-minute walk test.
Interstitial lung diseases include nonspecific interstitial pneumonitis, usual interstitial pneumonitis and lymphocytic interstitial pneumonitis. Other rare lung manifestations have been described in patients with pSS, such as amyloidosis, granulomatous lung disease, pseudo-lymphoma, pulmonary hypertension and pleural disease83. A persistent cough could be related to sicca or to bronchial involvement.
Antitussives — including inhaled glucocorticoids and β2-adrenergic agonists such as salbutamol — are used to treat pulmonary symptoms in pSS, but their efficacy has not been proven in RCTs. Interstitial lung disease in patients with pSS is usually only moderately severe and requires no treatment82. Evaluation at 6-month intervals has been suggested for patients with CT-identified abnormalities affecting <10% of the lung tissue and a DLCO >65% in the absence of respiratory symptoms83. In more severe cases, oral or intravenous glucocorticoid therapy can be used. Mycophenolate mofetil and azathioprine are other treatment options for lung manifestations in pSS, but their use is based on empirical evidence. One case report suggests that tocilizumab could be effective in treating the pulmonary manifestations of pSS84, but further study is required. On the basis of phase III trials85,86, pirfenidone and nintedanib were approved by the US FDA in 2014 for the treatment of idiopathic lung fibrosis, heralding a new era in the management of this condition. These drugs might deserve evaluation as treatments for lung disease in pSS.

Renal involvement

Renal involvement is reported in 4–30% of patients with pSS87. The typical form is interstitial lymphocytic infiltration, which is responsible for acute or chronic tubulointerstitial nephritis; renal failure is rare87. Symptoms of renal involvement in pSS are common and include hypertension, proteinuria and renal failure88. Renal biopsy is necessary to confirm the diagnosis. The main clinical manifestation is distal renal tubular acidosis, which can induce not only mild symptoms (pain, fatigue, electrolyte disturbances, serum creatinine elevation and mild proteinuria), but also potentially severe complications such as Fanconi syndrome and hypokalaemic paralysis88. Acute or chronic tubulointerstitial nephritis with impaired tubule function is the most prevalent form of biopsy-proven renal involvement87.The distal tubule is more often affected than the proximal tubule87.
Tubulointerstitial nephritis is difficult to diagnose. Patients with pSS must therefore be screened every 1–2 years for low-molecular-weight proteinuria, bicarbonaturia, uricosuria, phosphaturia, glycosuria, hypokalaemia, nephrocalcinosis and acidosis. More rarely, pSS induces glomerular lesions, which cause renal failure and proteinuria related to immune complex deposition, B-cell activation, cryoglobulinaemia or monoclonal chain excretion. The typical form is membranoproliferative glomerulonephritis (MPGN), although cases of cryoglobulinaemic, extramembranous, and proliferative glomerulonephritis have also been reported89.
The treatment of renal involvement in pSS is neither well standardized nor supported by evidence from RCTs. Long-term bicarbonate and/or electrolyte supplementation is appropriate in most patients to prevent life-threatening complications. Glucocorticoids are a mainstay of the treatment of tubulointerstitial nephritis. Several immunosuppressant drugs have been suggested in the absence of guidelines or data from RCTs. Mycophenolate mofetil has shown some efficacy in one small study90. Despite some evidence of efficacy from small case series or case reports87, cyclophosphamide is no longer recommended in tubulointerstitial nephritis owing to its adverse effects. Rituximab is used in patients with proliferative lesions on the basis of efficacy in lupus nephritis91 and empirical evidence.
MPGN is a life-threatening condition and is therefore routinely managed with immunosuppressant medications. The induction phase consists of pulsed doses of intravenous glucocorticoids followed by oral glucocorticoids. Once remission is achieved, maintenance treatment is given. Either cyclophosphamide or azathioprine can be used to maintain remission, as both have been proved effective in lupus nephritis92,93. Other options such as plasma exchange, rituximab and mycophenolate mofetil could be considered given their lesser toxicity, although no guidelines are available for their use in pSS. An RCT assessing rituximab in lupus nephritis failed to demonstrate therapeutic effects91, contradicting several open-label and retrospective studies94,95. Despite this conflicting evidence, rituximab is still used in some patients with pSS-related nephritis.
In patients with pSS who have vasculitis (or other severe manifestations) as well as cryoglobulinaemia, pulsed glucocorticoid therapy combined with plasma exchange and rituximab are commonly used, although only on the basis of open-label and retrospective studies96.

Muscular involvement

Muscle pain in the absence of muscle weakness and without creatine kinase elevation indicates 'low activity' in the muscular domain of the ESSDAI. This symptom must be distinguished from chronic widespread pain, which is reported by 35–50% of patients with pSS and is often associated with sleep disturbances and fatigue97. In the absence of myositis or any clear pathophysiological explanation for chronic pain, the treatment of muscle pain in pSS relies on analgesics and resembles that of neuropathic pain. Myositis with muscle weakness not explained by glucocorticoid therapy or another illness is considered to indicate moderate or high activity (depending on the strength deficit and serum creatine kinase level) in the ESSDAI muscular domain. The diagnosis of myositis should be confirmed by biopsy, but electromyography and MRI can also be useful.
Despite the fact that no RCTs have evaluated the treatment of pSS-related myositis, glucocorticoids are used as the main first-line treatment for this manifestation. They are given orally or as intravenous pulses depending on the severity of the muscle involvement. Other immunosuppressive agents are often given concomitantly in patients with high disease activity, both to improve the response and to minimize the adverse effects of glucocorticoids. The first-line conventional immunosuppressant is methotrexate (7.5–15 mg per week initially and then up to 25 mg per week), which can be combined with induction glucocorticoid therapy98. When this strategy fails, alternatives include: azathioprine, which demonstrated very limited efficacy in an RCT in 16 patients99; mycophenolate mofetil, which was effective in open-label studies and case reports100; tacrolimus or ciclosporin; and intravenous immunoglobulin (IVIg). In addition, rituximab can be used alone or in combination with, for example, glucocorticoids101, and combined treatment with rituximab and standard-of-care immunosuppressants was effective in an RCT in patients with refractory polymyositis102,103, supporting its use in treating pSS-related myositis. Anti-TNF immunotherapy is not recommended, in the absence of proof of efficacy. Cyclophosphamide is used only in patients with concomitant severe interstitial lung disease on the basis of empirical experience.

Neurological involvement

Approximately 20% of patients with pSS experience neurological involvement104. The neurological manifestations cover a broad spectrum and precede the diagnosis of pSS in one-third of cases105. These manifestations reflect damage to the peripheral nervous system (for example, pure sensory neuropathy, sensorimotor neuropathy, neuronopathy, cranial nerve involvement, polyneuropathy, mononeuritis multiplex and polyradiculoneuropathy) or the CNS (for example, meningitis, meningoencephalitis, encephalitis, seizure, stroke, transverse myelitis and cerebral vasculitis). No RCTs have assessed treatments for pSS-related neurological disease. Here, we summarize therapies currently used for the most common neurological manifestations of pSS.
In peripheral neuropathies, glucocorticoid therapy is generally given orally, with dosages depending on disease severity. IVIg (2 g per kg) and glucocorticoids (either methylprednisolone 500 mg or prednisone equivalent 1 mg per kg per day; for 48 weeks) are recommended in chronic inflammatory demyelinating polyneuropathy106,107. Immunosuppressant drugs (such as azathioprine, mycophenolate mofetil and cyclophosphamide) are sometimes used for remission maintenance but in the absence of proof of efficacy. Rituximab has produced variable results108. Plasma exchange can be considered in patients with refractory disease and autoantibodies109.
Sensory ganglioneuronopathy or sensory ataxic neuropathy due to dorsal spinal root involvement manifests as early sensory ataxia with subacute asymmetric, non-length-dependent sensory impairment. Kinaesthetic sensation is severely impaired110. In patients with marked proprioception impairments, pseudo-athetosis of the fingers and toes can develop. This complication is severe and often refractory to treatment. Treatments used empirically to date include plasma exchange111, IVIg109, rituximab112, glucocorticoids and cyclophosphamide. Oral azathioprine has also been used with some success110.
Small-fibre neuropathy is a condition of unclear pathogenesis that is defined as a structural abnormality of small nerve fibres, with degeneration of the distal ends of unmyelinated C fibres and thinly myelinated Aδ fibres. This condition is diagnosed by quantification of the somatic intra-epidermal nerve fibres in skin biopsy samples113. Quantitative sensory testing can also determine the psychophysical thresholds for cold and warm sensations. Small-fibre neuropathy is difficult to diagnose. Patients often complain of neuropathic pain and exhibit spontaneous and stimulus-evoked positive sensory symptoms with thermal and pinprick hypoesthesia. However, other conditions such as venous insufficiency, spinal stenosis, myelopathy and psychosomatic conditions can mimic small-fibre neuropathy.
Autonomic syndrome is a more severe manifestation of small-fibre neuropathy. Patients with autonomic dysfunction as a major manifestation are given a diagnosis of autonomic neuropathy114, a condition that is associated with orthostatic hypotension, Adie's pupil, anhidrosis, tachycardia and gastrointestinal disturbances. Diagnosis is based on clinical signs and symptoms of small-fibre impairment, as indicated by alterations detected in small-fibre neurophysiological investigations and/or reduced intraepidermal nerve fibre density detected by skin biopsy, when these features occur in the absence of electroneuromyography abnormalities. Only symptomatic treatments are available to treat autonomic dysfunction in pSS. Drugs that have anti-cholinergic effects are used empirically, but such drugs can worsen sicca symptoms115. The pharmacological strategy also includes analgesics, antidepressants and gabapentinoids, in a manner similar to the treatment of fibromyalgia71.
CNS manifestations include asymptomatic and symptomatic brain lesions that are visible by MRI. Spinal cord involvement in pSS can resemble primary progressive multiple sclerosis, progressive myelopathy or transverse myelitis. High-dose glucocorticoid therapy is used empirically, as are various immunosuppressant medications if necessary. In carefully selected patients with neuromyelitis optica, early systemic glucocorticoid therapy (intravenous methylprednisone) alone or combined with other immunosuppressant drugs is given to induce remission, which is then maintained by use of mycophenolate mofetil or azathioprine. The presence of autoantibodies associated with neuromyelitis optica (that is, those targeting myelin oligodendrocyte glycoprotein and aquaporin 4) mandates close follow-up116. Other treatments for CNS manifestations in pSS are selected on the basis of disease severity. They include plasma exchange, rituximab117 and oral agents such as azathioprine118, mycophenolate mofetil and methotrexate. Combination therapies or biologic agents such as rituximab, tocilizumab and eculizumab are promising approaches that warrant evaluation in RCTs119.

Cryoglobulinaemia

Cryoglobulinaemia in pSS is probably related to long-term polyclonal B-cell activation and is associated with an increased risk of developing lymphoma120. Type I cryoglobulins are single monoclonal immunoglobulins linked to a B-cell lymphoproliferative disorder. Type II cryoglobulins consist of polyclonal immunoglobulin IgG with monoclonal IgM with rheumatoid factor activity. Type III cryoglobulins comprise polyclonal IgG and polyclonal IgM with rheumatoid factor activity120. pSS is typically associated with the presence of type II and type III cryoglobulins, a setting referred to as mixed cryoglobulinaemia120.
Life-threatening complications of cryoglobulinaemia are related to severe vasculitis or MPGN. Various clinical manifestations are associated with systemic vasculitis affecting small blood vessels, ranging from mild clinical symptoms (such as fatigue, purpura, Raynaud's syndrome and arthralgia) to severe manifestations (such as peripheral nervous system or CNS involvement and cutaneous necrosis) and life-threatening complications (including glomerulonephritis and widespread vasculitis). Patients with MPGN secondary to cryoglobulinaemia have reduced survival compared with patients with other renal manifestations120. Treatment of systemic manifestations related to cryoglobulinaemia depends on lesion severity and can involve the use of glucocorticoids (usually administered in pulsed doses initally), immunosuppressant drugs (such as cyclophosphamide), plasma exchange, rituximab, azathioprine or mycophenolate mofetyl. In systemic vasculitis, a combination of plasma exchange and rituximab gives a good renal prognosis121. On the basis of retrospective studies concerning cryoglobulinaemia122,123, rituximab has become the cornerstone of treatment for the systemic manifestations of pSS-associated cryoglobulinaemia121, although its superiority over other immunosuppressants has not been demonstrated in RCTs.

Life-threatening manifestations

Life-threatening manifestations are rare in pSS and usually related to cryoglobulinaemic vasculitis or lymphoma124, as well as CNS involvement and ganglionopathies. Few studies have evaluated the efficacy of treatments for these manifestations in the context of pSS. Current practice relies mainly on case reports, data from similar diseases (vasculitis and SLE) and expert opinion. The treatments are organ-specific and consist mainly of immunosuppressant medications and high-dose glucocorticoids. In severe vasculitis or CNS involvement, methylprednisolone and cyclophosphamide pulses should be used, combined with intravenous immunoglobulins or plasma exchange in the most severe cases.
Lymphoma is one of the most serious complications of pSS, and its diagnosis is difficult. Lymphoma develops predominantly in the major salivary glands, but it can also arise in other mucosal tissues (for example, in lymphoid organs, the thyroid gland and the stomach). The standardized incidence ratio of lymphoma in patients with pSS is 4.9–9 in the most recent studies125,126. In pSS, low-grade extranodal marginal zone B-cell non-Hodgkin lymphoma (also known as mucosa-associated lymphoid tissue (MALT) lymphoma) is the most common variant. Ultrasonography of the salivary glands can be helpful to guide a biopsy and to evaluate the size of the gland and location of the nodes. PET-CT should be used as a means of detecting disseminated lymphoma foci.
Both diagnosis of MALT lymphoma due to pSS and evaluation of the risk of its development are difficult, and are based on expert opinion and the exclusion of other aetiologies. The treatment of MALT lymphoma is difficult to standardize because this tumour is often indolent and the prognosis often good. Available strategies include surgery, radiotherapy, and chemotherapy and rituximab (alone or in combination). Close monitoring without treatment might deserve consideration in some cases127.
When treatment is required in patients with pSS and MALT lymphoma, it should be tailored to each individual patient and based on the size of the involved gland, the number and location of the tumours, lymphadenopathy, international prognostic index, ESSDAI, and Helicobacter pylori status128, although H. pylori eradication has not been evaluated in clinical trials as a therapeutic approach to pSS-related lymphoma.
Despite the fact that not enough data support its use, rituximab is sometimes prescribed for MALT lymphoma. The treatment of salivary gland MALT lymphoma relies on rituximab combined with alkylating agents (for example, bendamustine or fludarabine with or without cyclophosphamide), but some patients have been managed with rituximab alone. In an RCT in patients with indolent lymphoma, including 67 with non-gastric MALT lymphoma, the combination of rituximab plus bendamustine was superior to the combination of rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy in terms of patient survival and toxicity129.
Other lymphoma subtypes such as lymphoplasmacytoid and diffuse large B-cell lymphoma also occur at higher rates in patients with pSS126. They are believed to arise from the transformation of previous low-grade lymphomas in about 10% of cases126. The treatment of these aggressive lymphomas should be adapted to the histological grade and relies mainly on rituximab combined with the CHOP regimen130.

Status of biologic therapies for pSS

As discussed above, the role for biologic agents in the treatment of pSS remains controversial. Although most open-label studies of biologics in pSS have reported efficacy61,62,131,132, the primary efficacy endpoint was not met in seven of the eight published RCTs of biologics in pSS; the exception was a small single-centre study of rituximab, the results of which were not replicated in two larger RCTs (Table 3).
The most commonly used inclusion criteria for RCTs evaluating biologic agents for the treatment of pSS were the American–European Consensus Group Sjögren's syndrome classification criteria,4 which were published in 2002, 10 years before the ACR criteria. Some studies also required the presence of salivary-gland biopsy abnormalities, the presence of anti-SSA/Ro or anti-SSB/La autoantibodies, or a decreased salivary flow rate. Composite inclusion criteria were used in some of RCTs. All of the RCTs published to date (Table 3) were designed and/or conducted before the publication of the ESSDAI and ESSPRI in 2014.
The lack of efficacy of TNF antagonists in pSS RCTs is unsurprising given the absence of a sound underlying pathophysiological rationale. By contrast, strong evidence supports a role for B cells in pSS, and open-label studies have consistently suggested benefits from B-cell depletion with rituximab96,133. Rituximab significantly improved not only the primary outcome (sicca), but also fatigue and extraglandular manifestations (ESSDAI), in a study from Netherlands39 and showed trends towards effects on fatigue and sicca in the TEARS RCT41. A post hoc analysis of the TEARS trial results suggested that selection of the primary endpoint can affect the interpretation of efficacy data and that subgroups of patients should be identified for future studies134. However, the TRACTISS RCT, conducted in the UK and presented as a late-breaking abstract at the 2015 ACR meeting, found no beneficial effects of rituximab63,64. Until the TRACTISS trial is published in full and its data analysed concomitantly with those from the TEARS trial, rituximab should probably not be used in pSS, except in patients with severe disease and no other treatment options.

Potential treatment targets

Potential targets for future therapies can be identified based on knowledge about the immunopathological mechanisms involved in pSS; this section provides an overview of these mechanisms (see also Supplementary information S1 (table)). Lymphocytic infiltration is the histological hallmark of pSS. Mild focal infiltrates do not considerably impair the organization of the lachrymal or salivary glands, whereas severe diffuse lesions disrupt the architecture of the duct epithelium and gland parenchyma. T cells and B cells comprise the vast majority of the mononuclear cells infiltrating the salivary and lachrymal glands (>90% of infiltrating mononuclear cells); infiltrates in the salivary glands are composed of 25–75% T cells (of which 50–70% are CD4+) and 20–60% B cells120. B cells predominate in advanced lesions135. The abundance of macrophages and dendritic cells ranges from 0.3% to 15% and 0.2% to 9%, respectively135.
Salivary-gland epithelial cells are also involved in the immunopathogenesis of pSS. Compared with salivary-gland epithelial cells from healthy controls, those from patients with pSS show reduced global DNA methylation, which could explain the aberrant transcription of many genes by these cells136. This global DNA demethylation was associated with decreased expression of mRNA transcripts encoding the methylating enzyme DNMT1 and increased expression of its demethylating partner growth arrest and DNA damage-inducible protein GADD45α136. Epithelial cell apoptosis induced by the infiltrating lymphocytes is considered a key factor contributing to the decreased production of exocrine secretions. Signalling of Fas ligand (FasL; also known as TNF ligand superfamily member 6) through Fas (also known as TNF receptor superfamily member 6) could explain the increased epithelial cell apoptosis mediated by T cells137, and B cells can directly induce epithelial cell death through a pathway involving translocation of protein kinase Cδ (PKCδ) into the epithelial cell nucleus138. In addition, several Toll-like receptors (TLRs) — including TLR2, TLR3, TLR4 and TLR7 — are expressed by epithelial cells in salivary-gland tissue139,140. TLR signalling in salivary-gland epithelial cells upregulates their expression of MHC class I, intercellular adhesion molecule 1 (ICAM1; which interacts with CD11a), CD40, Fas-associated proteins, CD80, and CD86, thereby linking the innate and adaptive immune responses139. Salivary-gland epithelial cells expressing CD86 possess distinctive binding properties, as indicated by preferential binding to the co-stimulatory molecule CD28 and reduced binding to cytotoxic T-lymphocyte antigen 4 (CTLA4)141.
Cytokine signalling also influences epithelial cell activation: IFNγ increases MHC class II expression by epithelial cells, enhancing antigen presentation to T cells142, and IFNγ and IL-1β induce CD40 expression by epithelial cells143. Epithelial cells might present nuclear autoantigens such as the SSA/Ro and SSB/La ribonucleoproteins to T cells144, and antigen presentation may be enhanced in the lachrymal glands in pSS owing to increased activity of cathepsin S145, which promotes the migration of MHC class II complexes to the cell surface for presentation. Epithelial cells also produce chemokines such as CXC-chemokine 13 (CXCL13), CC-chemokine 19 (CCL19) and CCL21, which promote lymphocyte migration into the salivary glands146.
Transcriptome analyses of salivary-gland tissue and mononuclear cells from patients with pSS have shown overexpression of type I IFN-induced genes147. Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit-δ (PI3Kδ) is activated by TLR stimulation and is required for type I IFN production148. One of the most relevant IFN-induced genes encodes BAFF and its overexpression is a hallmark of pSS149. Compared with normal levels of BAFF expression, BAFF overexpression could enable autoreactive B cells to survive increased levels of autoantigen-triggered death signalling and thus promote autoantibody production. The contribution of BAFF to the pathogenesis of pSS has been established in Baff-transgenic mice that develop several clinical features of Sjögren syndrome including salivary-gland inflammation150. BAFF levels are elevated in the serum and salivary glands of patients with pSS, and are associated with increased production of autoantibodies such as anti-SSA/Ro and anti-SSB/La antibodies and rheumatoid factor151,152. BAFF might also have a role in the pathogenesis of lymphomas associated with pSS153,154. Germinal centre-like structures are found in salivary-gland tissue from 25% of patients with pSS, and could be involved in disease pathogenesis in these patients10.
In combination with lymphotoxin-β (LTβ), LTα enhances ectopic lymphoid neogenesis155. Interestingly, terminal differentiation of B cells to plasma cells and memory B cells occurs within germinal centres under the supervision of T follicular helper (TFH) cells156. IL-21 production by dendritic cells contributes to maintaining the terminal differentiation of TFH cells157. In addition, cytokines produced by T helper 2 (TH2) cells are central in maintaining B-cell function. TH2 cells produce a vast array of cytokines including IL-4, IL-5, IL-6 and IL-13. Other cytokines are also implicated in pSS; for example, high levels of IL-17 have been found in serum and saliva samples, and IL-17-producing T cells and epithelial cells are present within inflammatory lesions of patients with Sjögren syndrome158,159,160,161. Research into the possible role of IL-17 in the immunopathogenesis of Sjögren syndrome is increasing. IL-17 might drive the differentiation of stromal cells into CXCL12-expressing cells, which enable follicle formation even in the absence of follicular dendritic cells and promote the formation of ectopic germinal centres in pSS162.
Although B-cell overactivity is evident in pSS, a role is emerging for a new category of B cells known as B regulatory (BREG) cells, which can blunt the development of autoimmune disorders163. The CD40–CD40 ligand (CD40L) interaction between B cells and T cells is critical for the acquisition of BREG-cell function upon TH1-cell differentiation through the production of IL-10, IL-35 and transforming growth factor-β (TGFβ) or indoleamine 2,3-dioxygenase164,165,166. Various chronic inflammatory environments that can occur in pSS have been reported to induce BREG cell populations, and BREG cells seem to be efficient at controlling T-cell proliferation and TH1-cell differentiation in patients with pSS164,167. Consequently, the depletion of BREG cells could explain the limited efficacy of global B-cell depletion in pSS41.
Further research into the role of BREG cells and other mechanisms involved in the immunopathogenesis of pSS is needed; however, as mentioned, our current knowledge highlights several potential therapeutic targets, some of which are being explored in clinical trials (see the next section). Other potential targets identified from the above discussion include CD80, CD86, cathepsin S, CD28, type I interferon, IFNγ, proinflammatory cytokines and chemokines.

Ongoing RCTs of new drugs

The emergence of biologic agents has expanded the therapeutic armamentarium available for pSS, and many pharmaceutical firms are showing interest in developing new drugs for pSS. Several ongoing RCTs are evaluating new drugs that target molecules implicated in the pathogenesis of pSS, including IL-6, CTLA4, CD40, BAFF, B7-related protein (also known as ICOSL), CD11a, lymphotoxin-β receptor (LTβR) and PI3Kδ (Table 4).
Table 4
Ongoing randomized controlled trials in primary Sjögren syndrome
Drug(s)
Mechanism of action
Inclusion criteria
n
Primary endpoint
Responsible party
Tocilizumab
Humanized monoclonal antibody targeting IL-6
2002 AECG criteria and anti-SSA/Ro or anti-SSB/La antibodies and ESSDAI score ≥5
110
ESSDAI
Hôpitaux Universitaires de Strasbourg, France
Abatacept
Fusion protein composed of the Fc region of IgG1 fused to the extracellular domain of CTLA4
2002 AECG criteria and ESSDAI score ≥5
88
ESSDAI
University Medical Center Groningen, Netherlands
CFZ533
Monoclonal antibody that binds CD40 and prevents its binding with CD40L
2002 AECG criteria and ESSDAI score ≥6
42
ESSDAI
Novartis
VAY736
Fully human monoclonal antibody targeting BAFFR
2002 AECG criteria and ESSDAI score ≥6; elevated serum ANA titres at screening (≥1:160); anti-SSA/Ro and/or anti-SSB/La antibodies; stimulated whole salivary flow rate at screening >0 ml per min
27
ESSDAI
Novartis
UCB5857
Small-molecule inhibitor of PI3Kδ
2002 AECG criteria and anti-SSA (Ro-52 and Ro-60) and/or anti-SSB/La antibodies
58
ESSDAI
UCB Pharma
AMG 557 (also known as MEDI5872)
Human monoclonal antibody targeting B7-related protein
2002 AECG criteria and ESSDAI score ≥6
42
ESSDAI
MedImmune
Belimumab and rituximab co-administration
Human monoclonal antibodies that inhibit BAFF and CD20, respectively
2002 AECG criteria and ESSDAI score ≥5; anti-SSA/Ro and/or anti-SSB/La antibodies; stimulated whole salivary flow rate at screening >0 ml per min or evidence of glandular reserve function (stimulated baseline salivary flow rate >0.05 ml per min); symptomatic oral dryness (≥5 out of 10 on patient-completed numeric rating scale)
70
Number of participants with AEs and SAEs
GlaxoSmithKline
Baminercept
LTβR fusion protein
2002 AECG criteria and stimulated salivary flow rate ≥0.1 ml per min (at screening); ≥1 systemic manifestation
72
Stimulated whole salivary flow
NIH National Institute of Allergy and Infectious Diseases
Low-dose IL-2
Regulatory T-cell response
2002 AECG criteria and ESSDAI score ≥6
60
ESSDAI
Jing He, Peking University, China
Efalizumab
Humanized anti-CD11a with an effect on ICAM1
2002 AECG criteria and one or more of the following: ESR >25 mm per h for men or >42 mm per h for women; serum IgG level ≥1,750 mg per dl; serum CRP level ≥0.8 mg per dl; stimulated salivary flow rate ≥0.1 ml per min; minor salivary gland biopsy with a focus score ≥4; ocular staining score ≥3 in at least one eye at study inclusion
10
Improvement in two or three of: salivary flow, salivary gland biopsy and tear flow
Gabor Illei, NIH Clinical Center, USA
AE, adverse event; AECG, American–European Consensus Group; ANA, antinuclear antibody; BAFF, B-cell-activating factor; BAFFR, BAFF receptor; CD40L, CD40 ligand; CRP, C-reactive protein; CTLA4, cytotoxic T-lymphocyte antigen 4; ESSDAI, EULAR Sjögren's Syndrome Disease Activity Index; ESR, erythrocyte sedimentation rate; IgG, immunoglobulin G; LTβR, lymphotoxin-β receptor; PI3Kδ, phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit-δ; pSS, primary Sjögren syndrome; SAE, serious adverse event; SSA, Sjögren syndrome-related antigen A; SSB, Sjögren syndrome-related antigen B.

Future perspectives

Approaches to trial design

That no systemic treatments have been proven effective in multicentre RCTs could be explained not only by true lack of efficacy, but also by poor selection of treatment endpoints and/or patients. Consequently, no conclusive evidence is available on the effect of disease activity, assessed using the ESSDAI, on the risk of further damage. In pSS, with a few exceptions, no specific manifestations (such as arthritis, skin lesions and interstitial lung disease) have been proven to result in damage; for example, arthritis is non-erosive.
Attempts to identify endpoints for clinical trials of drug efficacy face huge problems, and biomarkers that would help to evaluate treatment responses are lacking168. The treatment goal is a key consideration. Thus, appropriate endpoints for moisturisers, tear substitutes and secretagogues designed to relieve sicca could include patient-reported sicca symptoms (VAS scores) salivary flow rate; and results of Schirmer's test and the corneal test; endpoints for biologic drugs targeting glandular manifestations could include salivary gland size, inhomogeneity (assessed by ultrasonography) and histopathology169; endpoints for biologic or synthetic disease-modifying drugs targeting extraglandular manifestations could include patient-reported outcomes (ESSPRI) and disease activity (ESSDAI); and endpoints for long-term outcomes could include risk of lymphoma, dental health, and organ damage such as neuropathy.
One approach to evaluating pSS combines subjective and objective non-severe signs in patients and adds the ESSDAI in patients with systemic manifestations. In 2014, Cornec et al.170 built a composite endpoint based on a post hoc analysis of the TEARS trial. This endpoint, the Sjögren's syndrome responder index (SSRI)41,170, is based on five outcome measures: patient-assessed VAS scores for fatigue, oral dryness and ocular dryness; unstimulated whole salivary flow rate; and erythrocyte sedimentation rate. The SSRI does not reflect the clinical extraglandular manifestations of the disease but a mixture of subjective and objective signs of the disease. An SSRI-30 response is defined as ≥30% improvement in at least two of the five outcome measures. Studies are needed to assess the usefulness of the SSRI in future trials in pSS.
Another approach to pSS evaluation could be to focus on a single endpoint in a uniform patient population. However, this approach would be feasible only for treatments targeting common systemic manifestations of pSS. For evaluating the salivary glands, an ultrasonography score deserves consideration as an endpoint. Currently, the ESSDAI and ESSPRI are the two best-validated tools and are considered the reference standards for evaluating pSS. Most clinicians consider the use of biologics mandatory for patients with an ESSDAI score >5, but most patients with an ESSPRI score >5 are also willing to be treated with these drugs, as the impairment of quality of life is linked more closely to the ESSPRI than to the ESSDAI.
Another challenge faced when evaluating treatments for pSS is the selection of patients for inclusion in studies. Patient selection should be based on the study endpoint. According to one opinion, biologic therapy should be reserved for patients with systemic manifestations (high disease activity), whereas, according to another opinion, poor quality of life in any pSS variants warrants biologic treatment. Patients with high disease activity (symptoms and objective signs) and limited damage (as is probably more common in early disease) could be the best candidates for trials of biologic drugs. However, <10% of patients with pSS have symptom onset within the past 4 years, systemic disease, at least two of three VAS scores (for dryness, pain and fatigue) greater than 50 out of 100, and biological evidence of disease activity168. Similarly, only ∼10% of patients have an ESSPRI score ≥5, an ESSDAI score ≥5, an unstimulated salivary flow rate >0, and positive tests for anti-SSA/Ro antibodies171. Another important point is that the treatment parameters (such as the target, drug and dosage) differ between patients with B-cell and/or T-cell overactivity134.
In sum, patient-reported outcomes are currently evaluated on the basis of the ESSPRI, objective sicca symptoms (saliva and tear production), and complications (such as corneal changes), whereas the assessment of extraglandular manifestations relies on the ESSDAI. Most pharmaceutical firms confine their studies to patients with high disease activity (ESSDAI score >5). However, improved assessment tools and subgroup definitions could improve the evaluation of new biologic therapies. Among ongoing studies of biologic drugs for pSS, most use the ESSDAI as the primary endpoint. If these studies demonstrate efficacy, the ESSDAI will be used as the endpoint in further work. If not, attention will probably shift to increasing the uniformity of patient populations and/or selecting other primary endpoints. Concerning safety, consideration of the benefit:risk ratio will be important for biologic agents, as it is for other treaments.

Moving towards precision medicine

In addition to optimizing trial design, another aim for future research in the pSS field is to identify specific molecular signatures that will enable clinicians to select treatments that target the specific pathways involved in an individual patient's disease. There is a pressing need for studies using the available high-throughput 'omics' technologies (including genomics, transcriptomics, epigenetics, metabolomics and proteomics) and bioinformatics to identify biomarkers, which will be valuable for creating and implementing precision-medicine strategies. It can be hoped that the Innovative Medicines Initiative PRECISESADS (Molecular Reclassification to Find Clinically Useful Biomarkers for Systemic Autoimmune Diseases) consortium will strive towards the common goal of providing practical and clinically relevant treatments.

Conclusion

In 2016, we have a well-accepted but non-validated platform on which to build treatment strategies for pSS. At present, the role for biologic therapies is small; even the most extensively investigated biologic drug, rituximab, has failed to demonstrate superiority over placebo in RCTs (Table 3). However, some tools are now available for evaluating new treatments in pSS, and many potential treatment targets have been identified. Patients with pSS who fail to respond to conventional treatment, as well as those patients who respond well to conventional treatment but seek further symptomatic relief, should be invited to participate in ongoing RCTs.

Acknowledgements

The authors thank all members of the Brest Diagnosis Primary Sjögren Cohort Study Group: D. Cornec, S. Jousse-Joulin, T. Marhadour, D. Guellec, S. Boisramé-Gastrin, B. Cochener, M. Roguedas-Contios, M. Chastaing, V. Griner-Abraham, F. Couturaud, J. B. Noury, S. Genestet, C. Hanrotel, Y. Renaudineau, P. Marcorelles, S. Costa and Y. Gauvin.

Competing interests

J.-O.P. declares that he has received honoraria from Novartis. A.S. declares that he has received funds or honoraria from Abbvie, Bristol Myers Squibb, Chugai, GlaxoSmithKline, MSD, Novartis, Pfizer, Roche and UCB.. V.D.-P. declares that she has received funds or honoraria from Abbvie, Bristol Myers Squibb, Chugai, MSD, Novartis, Roche and UCB.
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