a modest decrease in B-cell numbers and acts as an immunomodulator. Epratuzumab is also less immunogenic with reduced potential for human anti-human antibody (HAHA) development and therefore suitable for repeated dosing in patients with chronic autoimmune diseases [26].

Sixteen patients in an open-label phase I/II study received four infusions of epratuzumab (360 mg/m2) at weeks 0, 2, 4, and 6 and were followed over a 6-month period. A composite endpoint involving the Schirmer-I test, unstimulated whole salivary ßow, fatigue VAS, and the laboratory parameters (erythrocyte sedimentation rate and IgG) was used to deÞne clinical response. Twenty percent improvement or more in at least two of the parameters constituted a clinical response. Of all the patients who received at least one dose of epratuzumab, 53% achieved a clinical response at 6 weeks, 53% at 10 weeks, 47% at 18 weeks, and 67% at 32 weeks. Peripheral B-cell levels were decreased by 54% at 6 weeks and 39% at 18 weeks. T- cell levels, immunoglobulins, and routine safety parameters did not change signiÞcantly [27]. Epratuzumab is a promising therapy, however, randomized, placebo-controlled trials are needed to conÞrm therapeutic efÞcacy.

32.7BAFF Inhibition

BAFF (B-cell-activating factor or B-lymphocyte stimulator, BLys) is a cytokine necessary for B- cell survival and maturation. BAFF may have a major role in SjšgrenÕs syndrome pathogenesis by regulating B-cell activation and autoantibody activation [28]. BAFF-transgenic mice develop severe sialadenitis, decreased saliva production, and destruction of submaxillary glands. Agents that inhibit BAFF and a related molecule (APRIL) could be an effective in SjšgrenÕs syndrome. Monoclonal antibody blockade of BAFF (belimumab, Lymphostat B) has shown activity in RA and lupus and is worthy of further consideration in SS, as are soluble receptor antagonists BAFF-R3 Ig and TACI Ig.

32.8Interferon Inhibition

Interferons are proteins with anti-viral activity and strong immunomodulating properties. Patients with SjšgrenÕs syndrome have an activated type I interferon system that includes IFN-α among other interferons. IFN-α improves phagocytic antigen processing and immunoregulatory activity of macrophages and speciÞc cytotoxicity of lymphocytes for target cells and natural killer cell activity [29]. It has been postulated that viral infection may initiate the production of IFN- α, however, continued IFN-α synthesis may be caused by nucleic acid-containing immune complexes that activate plasmacytoid dendritic cells to produce IFN-α at the tissue level [30]. Much recent work has underscored the importance of a type I interferon ÒsignatureÓ in SLE, with many patients exhibiting increased transcription of type I IFNs and of genes regulated by these cytokines [31]. In SLE, disease activity parallels the activation of these genes. Patients with primary SjšgrenÕs syndrome also show increased IFN-related gene activation [32]. It is reasonable to propose that agents that inhibit the action or production of interferon-α may have a therapeutic role in SLE or SjšgrenÕs syndrome. Receptor antagonists that prevent uptake of immune complexes by dendritic cells, inhibitory oligonucleotides that block binding of internalized DNA or RNA to Toll-like receptors, soluble IFN-α receptor, anti-IFN-α antibodies, or agents that block the signal transduction downstream of IFN- α receptors are potential targets of therapy.

Two monoclonal antibodies to type I interferon are in clinical trials in SLE. Preliminary reports have emphasized the apparent safety of this approach and have hinted at its efÞcacy in SLE [33]. Further studies are required to determine whether this approach will be of value in SjšgrenÕs syndrome.

It is of interest that there have been reports that low doses of IFN-α administered via the oromucosal route increase unstimulated salivary output. A phase II study showed that administration of low doses of IFN-α by dissolving

lozenges was safe and improved salivary output as well as decreased complaints of xerostomia [34]. These results prompted a randomized, double-blinded, placebo-controlled clinical trial with 497 patients. The patients in the treatment arm received a 24-week daily treatment of 450 IU IFN-α via the oromucosal route. The study failed to demonstrate a signiÞcant effect on VAS score for oral dryness and stimulated whole salivary ßow. However, there was a signiÞcant increase in unstimulated whole saliva in the patients treated with IFN-α [34].

These results seem contradictory to the postulated role of IFN-α in SjšgrenÕs syndrome. A potential explanation is that oral IFN-α treatment increases saliva secretion via up regulation of transcription of aquaporin 5, a membrane water channel, without inßuencing the underlying autoimmune process that could still be maintained by IFN-α. Further research is needed to fully understand the effect of IFN-α on salivary gland tissue and in SjšgrenÕs syndrome.

32.9Gene Therapy

Biologic agents generally have short half-lives and patients require frequent injections or infusions, which can be inconvenient and uncomfortable. Gene therapy offers the opportunity for stable and regulated expression of a therapeutic protein. There have been gene transfer studies conducted on animal models of SjšgrenÕs syndrome; however, no gene transfer studies have been conducted in human patients with SjšgrenÕs syndrome. Several gene delivery systems are available. They include recombinant viral vectors such as adeno-associated virus (AAV) and non-viral methods such as plasmidÐcationic liposome mixtures, DNAÐprotein conjugates, and naked DNA. The recombinant serotype 2 adenoassociated virus vector (rAAV2) has been successfully used in animal models of SjšgrenÕs syndrome [29]. Several successful examples of gene therapy in animals exist.

Local human IL-10 gene delivery to the submandibular glands in female non-obese diabetic (NOD) mice with SjšgrenÕs syndrome resulted in

increased salivary ßow rate and less focal inÞltration in the submandibular glands. Prophylactic adenovirus-mediated viral IL-10 delivery to the lacrimal gland partially suppressed the appearance of SjšgrenÕs syndrome-like features, such as reduced tear production, accelerated tear breakup time, and ocular surface disease [35]. An adenovirus encoding a human TNF receptor was used in a dacryoadenitis rabbit model. Prophylactic administration to the lacrimal glands with concurrent induction of dacryoadenitis led to a partial suppression of SjšgrenÕs syndrome-like features [36]. Administration of a rAAV2 vector encoding TNF receptor to the submandibular glands of the NOD mice increased salivary ßow and reduced local inÞltration [16]. Delivery of vasoactive intestinal peptide (VIP) via a rAAV2 vector to the submandibular glands of NOD mice increased salivary ßow rate, reduced levels of IL-2, IL-10, IL-12, and TNF-α in the submandibular glands and decreased serum levels of the chemokine RANTES [37].

Although localized salivary and lacrimal gland gene transfers have been encouraging in animal models of SjšgrenÕs syndrome, the clinical application of gene therapy in humans with SjšgrenÕs syndrome is uncertain and still needs extensive research. However, gene therapy studies have been useful in providing additional insight into the pathogenesis of SjšgrenÕs syndrome.

32.10Other Targets for Biologic Therapy

Abatacept (CTLA-4 Ig) inhibits T-cell activation by binding to CD80 and CD86 on B cells, dendritic cells, and other antigen-presenting cells; it has been shown to be effective in rheumatoid arthritis [38]. The rationale for use of this agent in SjšgrenÕs syndrome derives from the observation of activated T cells within glandular tissue and from the presence of co-stimulatory- like molecules within SjšgrenÕs lesions [39]. Blocking of T-cell co-stimulation might reduce lymphocyte accumulation by interrupting T-cell production of chemoattractive cytokines and

chemokines and by reducing the degree of interactions between T cells and B cells or antigen-presenting cells. There are also conßicting reports regarding whether SjšgrenÕs disease patients have a genetic polymorphism in the CTLA-4 gene itself [40].

A potentially very interesting approach to SjšgrenÕs therapy is natalizumab (Tysabri), a monoclonal antibody to α4 integrin. This agent is believed to inhibit migration of lymphocytes from lymph nodes to active sites of inßammation by blocking intracellular adhesion. It has been used with success in multiple sclerosis [41] and in CrohnÕs disease [41] and seems especially well suited to SjšgrenÕs syndrome and other disorders of inappropriate lymphocytic inÞltration. While it is generally well-tolerated, enthusiasm for its use is tempered by rare cases of progressive multifocal leukoencephalopathy, a severe and often fatal neurological disease [41].

While not a biological therapy, FTY-720 (Þngolimod) has a similar mechanism of action, but acts by blocking binding to sphingosine receptors [42]. It is under evaluation for multiple sclerosis and other autoimmune diseases and may be worth considering for SjšgrenÕs syndrome.

Efalizumab (Raptiva) blocks the binding of leukocyte function-associated antigen-1 (LFA-1) to intercellular adhesion molecules (ICAM-1) [43]. It has a potent effect on lymphocyte trafÞcking and was approved for the treatment of psoriasis. An National Institute of Dental and Craniofacial Research (NIDCR) study of its effectiveness in primary SjšgrenÕs syndrome is underway. In April, 2009, Genentech voluntarily withdrew Raptiva from the market because of concerns about progressive multifocal leukoencephalopathy. Three conÞrmed and one possible case of this illness were reported in patients receiving this treatment. Further safety evaluation is underway for this agent.

Alefacept is a monoclonal antibody that blocks the interaction between LFA-3 and CD2, an accessory activation molecule on T cells [44]. Despite its potent effect on T cells and its in vivo depletion of CD4+ T cells, opportunistic infections are not common and the agent is effective

in psoriasis. Its use in SjšgrenÕs syndrome has not yet been evaluated.

Tocilizumab, currently approved for treatment of rheumatoid arthritis in some countries, is a monoclonal antibody which blocks binding of IL- 6 to its receptor [45]. As IL-6 may contribute to SjšgrenÕs syndrome inßammation [46], it is possible that this agent will prove to be of value in SjšgrenÕs syndrome therapy.

32.11Conclusions and Future Directions

Though data are still preliminary, it seems that B- cell depletion therapy of SjšgrenÕs syndrome is the most promising biological therapy. Blocking of TNF-α, at least using agents effective for other illnesses, seems ineffective. There is much to be done in the evaluation of other biological interventions for this illness, particularly in the area of therapies that interfere with lymphocyte migration and with the action of interferon. The next decade should see signiÞcant advances in the treatment of moderate-to-severe SjšgrenÕs syndrome with biological agents.

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Further Reading

1.Abdulahad WH, Meijer JM, Kroese FG, Meiners PM, Vissink A, Spijkervet FK, Kallenberg CG, Bootsma H. B-cell reconstitution and T-helper-cell balance after rituximab treatment of active primary SjšgrenÕs syndrome. Arthritis Rheum. 2011 Jan; 10. [Epub ahead of print]

2.Meijer JM, Pijpe J, Vissink A, Kallenberg CG, Bootsma H. Treatment of primary Sjogren syndrome with rituximab: extended follow-up, safety and efÞcacy of retreatment. Ann Rheum Dis. 2009 Feb;68(2): 284Ð5.