Quarterly Medical ReviewBiologic treatments in Sjögren's syndrome
Section snippets
Disease impact and the justification for biologic therapy in primary Sjögren's syndrome
It is straightforward to justify the use of expensive biologic therapies in pSS patients with severe systemic involvement who fail to respond to conventional immunosuppression, despite the rare but potentially serious side effects of biologic therapy. Similarly, the use of rituximab in treating B-cell lymphoma in pSS is now well established (see below). What is less clearcut is the role for biologic therapies in pSS patients with sicca syndrome and/or fatigue alone. One argument is that the
Therapies for sicca features
Patients with mild oral and/or ocular dryness may self-manage their symptoms e.g. with artificial tears such as hypromellose, sipping water frequently, using oral gels/sprays/lozenges and careful dental hygiene. More severe ocular dryness can be managed through careful eyelid hygiene, more regular use of preservative-free viscous artificial tears and blockage of the tear (run-off) ducts so as to keep tears on the surface of the eyes for longer. In the USA and Japan, ciclosporin eye drops are
Therapy of B-cell lymphoma in primary Sjögren's syndrome
Treatment of B-cell lymphoma in pSS varies from a ‘watch and wait’ approach in indolent, localized, MALT lymphoma, to aggressive chemotherapy combined with rituximab for disseminated and/or high-grade MALT or DLBC lymphoma [26], [27]. The most widely used chemotherapy regime is CHOP (Cyclophosphamide, Adriamycin, Vincristine and oral prednisolone), or, variants of this regime such as cyclophosphamide, vincristine, and prednisone (CVP) and for the past 5–10 years standard practice is to combine
Biologic therapies – Terminology
The term biological therapy is generally used to refer to large synthesized molecules such as monoclonal antibodies that are directed against specific targets (table I). In rheumatic diseases these targets are usually either molecules involved in the immune system such as cytokines, or surface molecules, cluster differentiation (CD) or receptors expressed on cells of the immune system such as B or T-cells. They have been in widespread clinical usage over the past decade. They are generally
Challenges in clinical trials of biologics in primary Sjögren's syndrome
As we move into the era of biologic therapies for pSS it will be a requirement to conduct randomized double-blind controlled trials to demonstrate the effectiveness of these therapies. This requires consideration of inclusion and exclusion criteria for such trials as well as of outcome measures and endpoints. In terms of inclusion and exclusion criteria, the issues will include the level of systemic involvement required (if any), whether to require the presence of serological features such as
Risks of using biologic therapies in primary Sjögren's syndrome and other conditions
Biologic therapies are expensive and not without potential risk. Anti-TNF therapy in RA is associated with an increased risk of infection [45], particularly of tuberculosis (TB) [46]. Rituximab in RA has so far not been associated with a major increased infection risk [47], which is encouraging. Serum sickness, which is characterized by fever, rash, and joint pains, can occur in patients who receive chimeric monoclonal antibody therapy and has been reported following rituximab therapy. There is
Rituximab in primary Sjögren's syndrome without lymphoma
Rituximab is already available and licensed for use in RA and lymphoma. The basic rationale for investigating the use of rituximab in pSS has already been described above and is also reviewed elsewhere [53]. In summary: the presence of hypergammaglobulinaemia, anti-Ro/La antibodies, cryoglobulinaemia, low complement C4 levels and hypergammaglobulinaemic purpura suggest B-cell involvement in the extraglandular features of pSS. The link between many of these features and the development of B-cell
Targeting other cytokines
Since Sjögren's syndrome includes both organ-specific inflammation within the exocrine glands and local and systemic B-cell hyper-reactivity, there is a pathologic basis for evaluating a broad range of possible therapeutic targets. As well as BlyS/BAFF, TNF-alpha, IL-1 and IL-6 a number of other conventional cytokines have been shown to be upregulated in the salivary glands in PSS [114], [115], [116], [117], [118], [119]. These include IL-2, IL-3, IL-4, IL-10, IL-15, IL-21, IL-22, TNF-R1 and
Targeting chemokines
Chemokines (small chemotactic cytokines) such as CXCL13 (B-cell attracting chemokine) and CCL21 (secondary lymphoid chemokine – a T-cell homing chemoattractant) are expressed in the lymphoid aggregates in PSS and may be potential therapeutic targets [133]. Other chemoattractants of lymphoid cells such as CCL22 (stimulated T-cell chemotactic protein-1/monocyte-derived chemokine) and CCL17 (thymus and activation-regulated chemokine) are expressed in the salivary glands of a majority of patients
Conclusion
The increasing number of biologic agents being developed for rheumatic and other inflammatory conditions is opening a new era of therapies directed against specific immune targets relevant to different components of disease pathogenesis in pSS, ranging from the systemic B-cell driven features at one end of the spectrum to the organ-specific ‘T-cell’ driven glandular lesions. Pilot clinical data for anti-B-cell therapy with rituximab is encouraging and suggests potential benefit in treating
Disclosure of interest
Dr Bowman consulted for Merck-Serono; chief investigator of the TRACTISS study of rituximab in Sjogren's syndrome – drug supplied by Roche Pharmaceuticals without charge.
Glossary
- AECG
- American–European consensus group
- BAFF
- B-cell activating factor
- BLyS
- B-lymphocyte stimulator
- CHOP
- cyclophosphamide, adriamycin, vincristine and oral prednisolone
- CVP
- cyclophosphamide, vincristine and prednisone
- DLBC
- diffuse large B-cell lymphoma
- ESSDAI
- EULAR Sjögren's Syndrome Disease Activity Index
- ESSPRI
- EULAR Sjögren's Syndrome Patient Reported Index
- EULAR
- European League Against Rheumatism
- FDA
- Food and Drug Administration (USA)
- HRQoL
- health-related quality of life
- IFN
- interferon
- MALT
- mucosa-associated lymphoid
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Cited by (15)
Fingolimod reduces salivary infiltrates and increases salivary secretion in a murine Sjögren's model
2020, Journal of AutoimmunityCitation Excerpt :In clinical trials, however, only rituximab shows promise thus far, and has mostly been studied in patients with late stage disease [35]. Currently approved therapies for early stage SJS target only symptoms of disease (e.g. artificial tears, oral gels/sprays/lozenges, muscarinic agonists pilocarpine and cevimiline) [36]. There is a need for newer, better-targeted therapies that help alleviate symptoms as well as target systemic manifestations of SjS and halt disease progression.
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2018, Medicine (United Kingdom)Novel Therapeutic Strategies in Sjögren's Syndrome: B-Cell Targeting
2016, Sjogren's Syndrome: Novel Insights in Pathogenic, Clinical and Therapeutic AspectsNew Biological Avenues for Sjögren's Syndrome
2016, Sjogren's Syndrome: Novel Insights in Pathogenic, Clinical and Therapeutic AspectsSjögren's syndrome
2014, Medicine (United Kingdom)Citation Excerpt :A number of studies have suggested increased expression of TLRs on salivary epithelial cells in pSS.24 Up-regulation of TLRs may in turn increase expression of adhesion molecules, such as ICAM-1, or cytokines such as IFN type 1, IL-6, IL-17, and IL-23.24 In theory, therefore, up-regulation of TLRs (e.g. by viruses) may trigger glandular inflammation and damage in pSS.
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2018, Lupus