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Ординатура / Офтальмология / Английские материалы / Sjögren's Syndrome Diagnosis and Therapeutics_Ramos-Casals, Stone, Moutsopoulos_2012.pdf

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42 Experimental Therapies in Sjögren’s Syndrome

603

a decrease in the level of rheumatoid factor following B cell depletion therapy with rituximab in primary SjS patients might be a useful serum parameter to assess the treatment effect [17, 18]. In addition, analysis of changes in immune activation markers, such as cytokines involved in lymphocyte activation and inﬂammation, might serve as a biomarker for responses to therapy or recurrence of disease.

42.2.3Labial or Parotid Tissue

Although both labial and parotid biopsies are valid to diagnose SjS [19], detailed immunohistopathologic analyses of parotid biopsies are particularly useful to correlate with clinical ﬁndings such as salivary ﬂow rate and the composition of saliva. The parotid gland can be sampled repeatedly through incisional biopsy procedures [16]. This approach is very useful when looking in detail into the assumed achievements of intervention therapies [15, 17, 20] and in getting insight into the mechanisms underlying the return of salivary secretion.

42.3Molecular Targets for Potential Therapeutic Interventions

Biological agents targeting speciﬁc molecules have been introduced in various systemic autoimmune diseases, in particular in rheumatoid arthritis (RA). Biological agents most frequently applied in autoimmune diseases are monoclonal antibodies, soluble receptors, and molecular imitators functioning as false ligands [21]. These biological agents enhance or replace conventional immunosuppressive therapy. In contrast to the situation with RA, no biological agent has yet been approved for the treatment of SjS, but several phase II and III studies have been or are currently being conducted (Tables 42.1 and 42.2) [22–25]. The biological agents used in SjS trials are interferon-alpha (IFN-a), agents that inhibit tumor necrosis factor-alpha (TNF-a), and agents that interfere with B cell function through either depleting or non-depleting mechanisms (anti-CD20, anti-CD22). Although no trials have yet been published with B cell activating factor (BAFF) antagonists and agents blocking co-stimulation, these pathways also offer promising therapeutic approaches [26]. A number of monoclonal antibodies against interleukins (IL) or IL receptors (IL-R) are currently under consideration for use in SjS. The same is true for monoclonal antibodies against IL-6, IL-6R, IL-7, IL-12/IL-13, and IL-17.

42.3.1Interferons

Interferons are proteins with antiviral activity and potent immunomodulating properties. SjS patients have an activated type I IFN system (Fig. 42.3) [27]. Such a role for IFN-a appears to contradict the reports described below purporting to indicate

604 A. Vissink et al.

Table 42.1 Cytokines as therapeutic targets for the treatment of SjS based on the availability and/ or development of cytokine-directed drugs [24]

		Rationale for blocking
Target	Main effect	in SjS	Stage of drug development

IFNa	Antiviral, proand	Decreasing inﬂamma-	Anti-IFNa monoclonal antibody:
	anti-inﬂammatory,	tion, reverse Th1	single dose suppressed
	important for NK	type immune	IFN signature in SLE, multiple
	cell activity	response.	dose phase I study completed
		Administration of	Administration of IFNa: multiple
		IFNa: enhancing	parenteral formulations
		NK cell activity?	approved, oral lozenge in
			clinical studies. In SjS, only an
			effect on salivary secretion was
			observed, not on the other SjS
			parameters assessed.
BAFF	B cell development,	Decreasing B cell	Phase III studies have shown
	maturation, survival	activation,	efﬁcacy in SLE. A study in SjS
		prevention of GC	is currently undertaken.
		formation and
		lymphomagenesis,
		reduction of
		autoantibodies
IL-6	B cell proliferation and	Decreasing systemic	Phase III studies in RA successfully
	plasma cell	and local inﬂam-	completed, pilot study in SLE
	formation, acute	mation, decreasing	showed normalization of B cell
	phase response, T	B cell activation,	repertoire
	cell stimulation and	decreasing plasma
	recruitment	cell formation,
		reduction of
		autoantibodies
IL-7	Growth factor in early	Decreasing proinﬂam-	Not yet available for administration
	T cell development.	matory and	in humans
	Stimulation of	tissue-destructive
	growth, prolifera-	responses
	tion, survival and
	differentiation of
	mature, naïve, and
	memory T cells
IL-12/	Differentiation into	Decreasing inﬂamma-	Phase III clinical trial in psoriasis
IL-23	Th1 type immune	tion, reduction of	successfully completed, phase II
	response	GC formation, and	for Crohn’s disease currently
		lymphomagenesis	undertaken
IL-17	Proinﬂammatory,	Reverse autoimmunity,	Phase II clinical trial for RA,
	clearing of	reducing	Crohn’s disease and psoriasis
	extracellular	inﬂammation	currently undertaken
	pathogens, major
	role in
	autoimmunity

BAFF B cell–activating factor, GC germinal center, NK natural killer, RA rheumatoid arthritis, SLE systemic lupus erythematosus, SjS Sjögren’s syndrome, Th1 T-helper type 1

42 Experimental Therapies in Sjögren’s Syndrome

605

Table 42.2 Potential B cell and T cell targets, monoclonal antibodies, and other treatments used for B cell depletion or modifying T cell stimulation in patients with SjS [25]

Direct targeting of B cells

CD-20 antigen

Rituximab (chimeric monoclonal antibody) Ocrelizumab (humanized monoclonal antibody) Ofatumumab (humanized monoclonal antibody) Veltuzumab (humanized monoclonal antibody) TRU-015 (engineered protein)

CD-22 antigen

Epratuzumab (humanized monoclonal antibody) Indirect targeting of B cells

B cell activator belonging to the extracellular TACI receptor domain (BAFF)

Belimumab (LymphoStat B: fully human monoclonal antibody against BAFF)

BAFF receptors

Anti-BR3

Atacicept (IgG Fc fused to the extracellular TACI receptor domain) Briobacept/B3-Fc (IgG Fc fused to the extracellular BAFF receptor, BR3 domain)

T cell–dependent activation of B cells

Abatacept (fully human soluble co-stimulation modulator) Direct targeting of T cells

IL-2Ra receptor

Basiliximab (chimeric monoclonal antibody) Daclizumab (humanized monoclonal antibody)

CD3

Muromonab (chimeric antibody)

CD52 (present on all lymphocytes)

Alemtuzumab (humanized monoclonal antibody)

TACI transmembrane activator and calcium modulator and cyclophylin ligand interactor

that low doses of IFN-a administered via the oromucosal route increase the unstimulated salivary output. It is hypothesized that oral IFN-a treatment acts by increasing saliva secretion via upregulation of aquaporin 5 transcription without signiﬁcantly inﬂuencing the underlying autoimmune process [27, 28].

In a number of phase II studies, treatment of primary SjS patients with IFN-a administered via the oromucosal route (by dissolving lozenges) was demonstrated to be effective and safe [29–32]. Manifestations of treatment efﬁcacy included improvement in salivary output and reduced complaints of xerostomia. Based on these promising results, a randomized, parallel group, double-blind, placebo-controlled clinical trial of 497 patients with primary SjS was conducted. This trial failed to demonstrate a signiﬁcant effect on the primary endpoints (visual analogue scale (VAS) for oral dryness and stimulated whole salivary ﬂow) in the IFN-a group relative to the placebo group, but there was a signiﬁcant increase in unstimulated whole saliva in the patients treated with IFN-a. This

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