How to Assess Treatment Efficacy in Sjo¨Gren's Syndrome?

REVIEW

CURRENT OPINION How to assess treatment efficacy in Sjo¨gren’s syndrome?

Arjan Vissinka, Hendrika Bootsmab, Frans G.M. Kroeseb, and Cees G.M. Kallenbergb

Purpose of review This article critically reviews the current views and discusses the future challenges with regard to assessing disease progression and disease activity in Sjo¨gren’s syndrome, as a decrease of disease progression and activity is what an effective Sjo¨gren’s syndrome therapy aims for. This topic has recently gained renewed attention as targeted treatment modalities have become available in primary Sjo¨gren’s syndrome, while the lack of well established outcome parameters interferes with a straightforward comparison of the outcomes of the various trials. Recent findings Recent advances in how to assess changes in disease progression and activity objectively (via repeated biopsies of salivary glands, sialometry, sialochemistry, biomarkers, secretion and composition of tears, EULAR Sjo¨gren’s Syndrome Disease Activity Index: ESSDAI) and subjectively (EULAR Sjo¨gren’s Syndrome Patient Related Index: ESSPRI) have opened new ways to reliably assess the outcome of a particular treatment. Summary Newly applied tools are instrumental, both for clinical research and clinical practice, in reliably judging and comparing the value of well established and newly developed therapies in Sjo¨gren’s syndrome. Keywords biologicals, ESSDAI, ESSPRI, saliva, Sjo¨gren’s syndrome, tears, treatment efficacy

INTRODUCTION studies which makes a proper comparison of results && & Sjo¨gren’s syndrome is an autoimmune inflamma- between studies difficult if even possible [7 ,8 ]. tory disorder of exocrine glands. It particularly Therefore, this study critically reviews the current affects the lacrimal and salivary glands. Dry mouth views and future challenges with regard to measur- and dry eyes are frequently proffered as presenting ing disease activity and disease progression in symptoms [1,2]. These symptoms are in many cases Sjo¨gren’s syndrome. accompanied by nonspecific symptoms, such as malaise and fatigue [3]. In addition, extraglandular PROGRESSION AND DISEASE ACTIVITY ¨ manifestations, like purpura, polyneuropathy, and IN PRIMARY SJOGREN’S SYNDROME arthritis, can be present, even as presenting signs of As mentioned in the introduction, the largest hurdle the disease [2]. Lymphomas develop in 5–10% of to be taken is to develop a reliable set of assessments Sjo¨gren’s syndrome patients [4,5]. Sjo¨gren’s syndrome affects mainly women with a female/male a b ratio of 9 : 1 and can occur at all ages. Department of Oral and Maxillofacial Surgery and Department of In-vitro and in-vivo experimental data have Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands pointed to new immunopathogenic mechanisms Correspondence to Arjan Vissink, DMD, MD, PhD, Department of Oral in primary Sjo¨gren’s syndrome (pSS). The availabil- and Maxillofacial Surgery, University Medical Center Groningen, ity of targeted treatment modalities has opened new University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The ways to selectively target these mechanistic path- Netherlands. Tel: +31 50 3613840; fax: +31 50 3611136; e-mail: ways in vivo [6&]. A problem of all studies assessing [email protected] the efficacy of these new modalities is the large Curr Opin Rheumatol 2012, 24:281–289 variety of outcome parameters used in the various DOI:10.1097/BOR.0b013e3283524c37

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Activity Index (ESSDAI) [12&,13&,25&] as there are for KEY POINTS rheumatoid arthritis (RA) [26] and systemic lupus ESSPRI and ESSDAI are promising tools to assess erythematosus (SLE) [27]. disease activity and disease progression in pSS to With regard to pSS, studies are in progress to monitor treatment efficacy. assess the reliability and sensitivity to change of the ESSDAI and ESSPRI. Such studies are important as Salivary gland functioning in pSS patients is best the usefulness of instruments designed to measure assessed by measuring glandular secretions and should be included in monitoring progression and treatment change over time or after therapeutic intervention is efficacy of pSS. not only dependent on their validity and reliability, but also on their potential to detect clinically Tear osmolarity may evolve into a more potent tool for relevant changes [28–30]. Seror et al. [12&] retrospec- assessing the ocular component in pSS than lisamin tively investigated the sensitivity to change of the green and Schirmer tests. ESSDAI over time in 96 patient profiles and reported Proteomic and genomic approaches in saliva and tears that the internal and external responsiveness of are potent tools to facilitate diagnosis, to monitor the ESSDAI was large, and changes over time were effect of a particular treatment, and to contribute to detected more accurately than with other known understanding of pSS pathogenesis. indices. Meiners et al. [31&&] prospectively assessed Labial or parotid biopsies are needed for proper the internal and external responsiveness to change diagnosis, as they may indicate the likelihood of of ESSPRI and ESSDAI in pSS patients treated with developing MALT or NHL lymphoma and thus may rituximab. The latter study revealed that ESSPRI indicate which patient has to be closely monitored. and ESSDAI are, indeed, sensitive to measure the Repeated (parotid) salivary gland biopsies may show changes in disease activity after therapeutic inter- what the treatment effect is at a tissue level. vention, which supports the usefulness of these indices for future clinical trials. The promising results from the retrospective analysis of Seror et al. [12&] and the prospective intervention study by which the efficacy of a particular treatment by Meiners et al. [31&&] showed that, when validated, approach can be assessed, meanwhile allowing evi- application of both instruments for outcome dence-based comparison of the various treatment measurements in randomized controlled clinical approaches tested in pSS [6&,7&&,8&]. Such a set of trials should allow assessing all aspects of pSS assessments probably also can be used to rate disease (Fig. 1). activity and disease progression in pSS. Saliva EULAR Sjo¨ gren’s Syndrome Disease Activity Within the wide spectrum of clinical manifestations Index and EULAR Sjo¨ gren’s Syndrome of Sjo¨gren’s syndrome, salivary gland dysfunction is Patient Related Index considered to be a key manifestation [32]. Dysfunc- Evidence-based therapy for Sjo¨gren’s syndrome is tion of the salivary glands results in changes of the largely limited to treatments that improve sicca amount and composition of the saliva. The auto- features [7&&,9–11]. In addition, the variety of ad immune process itself is reflected by the presence of hoc outcome measures used to rate the effects of various components of the immune response, such both symptomatic and disease-modifying treat- as cytokines, chemokines, autoantibodies, in saliva. ments are mainly based on glandular symptoms As such, sialometry is not only of diagnostic but also [12&,13&]. Therefore, validated activity indexes are of prognostic importance. Moreover, as the amount needed to assess the effectiveness of (new) targeted and composition of saliva reflect the damage caused therapies [14–16]. For example, B-cell-targeted by the autoimmune process in the salivary glands, therapies have shown promising results for both sialochemistry may be valuable in diagnosis, assess- systemic [17–22] and glandular features ment of prognosis, and evaluation of treatment [17,21,23,24&&], but, again, a variety of outcome [17,24&&,33–36]. Thus, sialometry and sialochemis- measures has been used [7&&,8&]. To solve these short- try can be used as a diagnostic tool either by collect- comings, the European League against Rheumatism ing whole saliva (the combined secretions of all (EULAR) recently introduced a patient-administered salivary glands) [37] or by collecting glandular saliva questionnaire to assess patient symptoms (EULAR (gland-specific saliva) [33,34,38,39]. Although Sjo¨gren’s syndrome Patient Reported Index: ESSPRI) unstimulated whole saliva is a major criterion for and a systemic activity index to assess systemic the evaluation of salivary gland dysfunction in complications (EULAR Sjo¨gren’s Syndrome Disease Sjo¨gren’s syndrome [37], when Sjo¨gren’s syndrome

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(a) Score 10 ESSPRI 9 ESSDAI 8 7 6 * ** * 5 4 3 2 ** * 1 0 0122436 48 60 Time (weeks) (b) Improvement 100 disease activity Constitutional 80 Glandular Articular 60 Haematological Biological 40

0 12 24 36 48 60 Time (weeks)

FIGURE 1. Disease activity in primary Sjo¨gren’s syndrome patients treated with rituximab (median values). (a) ESSPRI and ESSDAI. (b) Disease activity for the ESSDAI domains showing the highest changes (percentage of patients with no disease activity in a particular domain is given). ÃIndicates significant (P < 0.05) change compared with baseline [31&&]. develops, not all major salivary glands may yet recent progress in proteomics and genomics has manifest dysfunction, rendering whole saliva less shown that the proteomic and genomic profile valuable as a parameter for evaluating progression of reflecting the autoimmune process even might be the disease or therapeutic intervention than glan- more sensitive and specific in diagnosing Sjo¨gren’s dular saliva (Fig. 2) [35]. In contrast to whole saliva, syndrome [40–42,43&,44&]. In contrast to most other analysis of gland-specific saliva can reveal sequential diseases studied thus far, in which the majority of involvement of particular glands, reflecting the reports studying the same disease produced incon- ongoing autoimmune process in individual major sistent results to studies on biomarkers, proteomic salivary glands. By using glandular saliva, patients and genomic analyses of saliva in pSS were more with Sjo¨gren’s syndrome may frequently be diag- consistent [45,46]. nosed at an earlier stage, and progression and effects It has been studied whether biomarkers that dif- of therapeutic intervention can be measured in a fer between pSS patients and healthy individuals are noninvasive way. For example, Pijpe et al. [36] indeed specific for pSS or are also commonly showed that regeneration of salivary gland tissue expressed in saliva of patients with other auto- by rituximab was accompanied by an increase in immune diseases [46]. As a first step to look into salivary flow and normalization of salivary compo- the specificity of biomarkers for diagnosing Sjo¨gren’s sition (Figs 3 and 4). syndrome, the Sjo¨gren’s syndrome proteomic/ genomic profile was compared with that of SLE patients (all not fulfilling criteria for secondary Sjo¨g- Biomarkers in saliva ren’s syndrome). It was shown that three protein Although Kalk et al. [33,34] suggested stimulated biomarkers, namely, cathepsin D, alpha-enolase, submandibular/sublingual flow rate in combination and beta-2-microglobulin (B2M), and three mRNA with parotid sodium and chloride concentration as biomarkers in saliva, namely, myeloid cell nuclear a reliable diagnostic test for Sjo¨gren’s syndrome, differentiation antigen (MNDA), guanylate-binding

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Primary SS patients and controls Salivary secretion 0.6 (ml/min/gland)

0.5

0.4 Healthy controls = 1 year (n = 16) 0.3 1–4 years (n = 7) >4 years (n = 9) 0.2

0.1 ** * 0 UWS SM/SL SM/SL Parotid gland Parotid gland unstimulated stimulated unstimulated stimulated

Secondary SS patients and controls Salivary secretion 0.6 (ml/min/gland)

0.5

0.4 Healthy controls = 1 year (n = 11) 0.3 1–4 years (n = 9) >4 years (n = 8) 0.2

0.1 **

0 UWS SM/SL SM/SL Parotid gland Parotid gland unstimulated stimulated unstimulated stimulated

FIGURE 2. Relation between disease duration, that is, the time from first complaints induced by or related to oral dryness until referral, and mean salivary flow rates (mean Æ SEM). UWS, unstimulated whole saliva; SM/SL, submandibular/sublingual glands [35].

protein 2 (GIP2), and the low-affinity IIIb receptor The next step has to be to further test the for the Fc fragment of IgG (FCGR3B), were all sig- genomic and proteomic biomarkers in patients with nificantly elevated in pSS patients compared with pSS and RA, and to reveal biomarkers that can both SLE patients and healthy controls. The com- distinguish pSS from RA and from non-Sjo¨gren’s bination of cathepsin D, alpha-enolase, and B2M syndrome sicca patients. A validation study [47] yielded a receiver operating characteristic (ROC) sponsored by National Institutes of Health (USA) value of 99% in distinguishing pSS from healthy is currently underway. Moreover, proteomic/ controls.Thecombinationoftheproteinmarker, genomic analysis of pSS, followed by gene ontology B2M, and the mRNA biomarkers MNDA and GIP2 or functional pathway analysis, may also reveal reached a ROC of 95% in discriminating pSS from molecular targets and related pathways associated SLE [43&,44&]. with the disease pathogenesis. As such, these

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Ultrasound Before therapy After therapy The focus of ultrasound is not only how to diagnose PAR LEL pSS, but also how to rate the progression of the SD disease and thus might evolve into a tool to objectively assess a treatment effect [48–51,52&,53&]. GS Moreover, although the ultrasound image in major GS SD salivary glands affected by Sjo¨gren’s syndrome is rather characteristic, a current limitation is still that A1 CK14-Ki67 LEL B1 CK14-Ki67 the image is characteristic for the advanced stages of pSS and not for the very early stages of pSS. The GS better performance of submandibular ultrasound in A3CD3 B3 CD3 diagnosing Sjo¨gren’s syndrome is in agreement with the observation that submandibular/sublingual glands are earlier involved in Sjo¨gren’s syndrome GS than the parotid glands as based on sialometrical A2 CD20 B2 CD20 studies [33–35,38]. Moreover, parotid glands seem to have a greater reserve capacity than submandibular glands as, on a histopathological level, changes can already be observed in the parotid glands when the salivary flow is not yet significantly LEL affected [33–35,38]. This is also in line with parotid ultrasound findings, as changes in parotid salivary composition precede changes in parotid flow show- A4 CK14-Ki67 B4 CK14-Ki67 ing that the ductal system is primarily affected by the disease process. FIGURE 3. Comparison of parotid biopsy specimens obtained from a pSS patient before rituximab therapy (A1– A4) and 12 weeks after therapy (B1–B4). A1, before Salivary gland biopsy treatment, double staining illustrates intense inflammation A widely accepted criterion for histological confir- (arrows) with highly proliferating, large germinal centers mation of Sjo¨gren’s syndrome is focal lymphocytic (GS; red nuclear staining for Ki-67), fully developed sialoadenitis in labial salivary glands [54,55]. In a lymphoepithelial lesions [LEL; brown staining for cytokeratin normal population, labial biopsy results in 6–9% 14 (CK14)], and reduced glandular parenchyma (PAR). B1, false-positive diagnoses, and 18–40% of patients After treatment, inflammation was reduced (arrows), with the with clinically diagnosed Sjo¨gren’s syndrome have absence of germinal centers and the presence of regular a negative labial biopsy [54–56]. An alternative to a striated ducts (SD) devoid of LELs. A2, Before treatment, labial biopsy is an incision biopsy of the parotid there was a dominance of B lymphocytes with germinal gland [57]. A major advantage of parotid biopsies centers (CD20) in comparison with T lymphocytes (CD3; over labial biopsies with regard to disease pro- A3). B2, After treatment, the lymphoid infiltrate overall was gression and assessing the effect of an intervention reduced, with a slight dominance of T lymphocytes (CD3; treatment is that parotid gland tissue can be har- B3) compared with B lymphocytes (CD20). A4, A higher vested easily, repeated biopsies from the same paro- magnification view shows fully developed LELs with many tid gland are possible, and the histopathological intraepithelial lymphocytes and increased basal cell results can be compared with other diagnostic proliferation (arrows), in contrast to the regular striated duct results derived from the same gland (e.g. secretory after therapy with CK14-positive basal cells (B4, arrows) function, sialographic appearance, and ultrasound) with regular differentiation into luminal ductal cells devoid of [36]. There are, however, also some differences intraepithelial lymphocytes (arrowheads) (original between labial and parotid biopsies as, for example, magnification 120Â in 1A1 and 1B1; 100Â in 1A2 and in contrast to labial glands, lymphoepithelial lesions 1B2; 60Â in 1A3 and 1B3; 200Â in 1A4 and 1B4) [36]. (LELs) are often observed in parotid gland tissue of Sjo¨gren’s syndrome patients [58]. Finally, by per- analyses may indicate the progression of the disease forming parotid biopsies as a routine diagnostic and serve as a measure for disease activity. In future, procedure for Sjo¨gren’s syndrome, lymphomas proteomic and genomic analysis also can be applied can be found at an earlier stage [59,60&&]. However, to rate whether therapeutic intervention has very rare, B-cell MALT lymphomas are occasionally resulted in arresting pSS or regeneration of diseased found in labial biopsies of Sjo¨gren’s syndrome tissues. patients [61,62&&]. Recently, it has been shown that

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Sodium concentration in parotid saliva

[Na] 20 (ml/min)

10 Patients Controls

0 Baseline Weeks 5 Weeks 12

FIGURE 4. Four out of the five patients included in the study of Pijpe et al. [36] (see also Fig. 3) showed a minor-to-moderate increase in the parotid salivary flow rate (mean increase 24%). The baseline sodium concentration in parotid saliva was increased in the saliva samples from these four patients (patient 5 had no parotid salivary flow at baseline). The sodium concentration decreased after treatment in all four of the above-mentioned patients, and values returned to near-normal in two of these four patients.

the presence of germinal center-like structures diag- of anti-La/SSB antibody and mean tear IL-17 con- nostic of salivary biopsies for pSS might be a highly centration were significantly higher in pSS patients predictive and easy-to-obtain marker for lymphoma with severe keratoconjunctivitis sicca. Thus, serum development. This observation allows the risk strat- anti-Ro/SSA antibody, serum anti-La/SSB antibody, ification of patients and the possibility to initiate and tear IL-17 are likely to be strongly involved in preventive B-cell-directed therapy [62&&]. It empha- the clinical severity of keratoconjunctivitis sicca in sizes the need to obtain salivary gland biopsies as a pSS patients [66&] and, thus, may have some poten- method to predict the risk of lymphoma [63&]. tial as a disease progression and treatment outcome monitor in pSS. Histological and functional changes of the Tears lacrimal gland might be reflected in proteomic Similarly to saliva, the amount and composition of patterns in tear fluids [67]. In a tear study [68], tears are not only influenced by damage of the multiple protein changes were reproducibly lacrimal glands, but also reflect the autoimmune detected in pSS patients, including 10 potential response itself. Regarding the dry eye, the use of novel biomarkers. Thus, the ability to probe the tear osmolarity in dry eye assessment has recently protein content of human tear fluid has enormous gained attention for diagnostics, monitoring disease potential for deepening our understanding of ocular progression, and treatment evaluation in pSS. Tear and systemic disease pathology and enabling novel osmolarity values were shown to be greater in noninvasive tear-based diagnostic technology using patients with dry eye syndrome related to pSS com- proteomic approaches and microfluidic homo- pared with control individuals, and positively corre- geneous immunoassays [69&]. For example, when lated with the severity of dry eye [64&,65&]. Measuring using the latter immunoassay, Karns and Herr osmolarity is simple and probably will become an [69&] were able to measure lactoferrin, a biomarker integral part of dry eye assessments in the clinical that is reduced in Sjo¨gren’s syndrome, in a very low setting. Osmolarity has the advantage of functioning volume of tears (<1 ml) which brings the use of tears as a noninvasive and easily performed objective to monitor Sjo¨gren’s syndrome disease activity and clinical biomarker for dry eye severity [64&]. Osmo- progression as well as to assess treatment outcome larity values of greater than 308 mOsms/l are gener- within reach for clinical application. ally indicative of dry eye disease (mild 308 mOsm/l; moderate 320 mOsm/l; severe >355 mOsm/l). Concentrations of autoimmune response Serum parameters as anti-Ro/SSA antibody and anti-La/ Serum may contain a variety of biomarkers related SSB antibody in serum are significantly higher in to the autoimmune process that can be used to pSS patients with severe keratoconjunctivitis sicca diagnose Sjo¨gren’s syndrome, to characterize disease than mild keratoconjunctivitis sicca. Also presence activity and progression in Sjo¨gren’s syndrome, to

286 www.co-rheumatology.com Volume 24 Number 3 May 2012 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Treatment efficacy in Sjo¨ grens syndrome Vissink et al. recognize Sjo¨gren’s syndrome patients who may antibody titer. Thus, upregulation of IFN-inducible develop extraglandular manifestations, to recognize genes in Sjo¨gren’s syndrome patients seems to be a Sjo¨gren’s syndrome patients with an increased risk systemic phenomenon and is in line with the notion to develop MALT lymphomas or non-Hodgkin that pSS patients have a type I IFN signature. Expres- lymphomas, and to evaluate the effect of an inter- sion levels of IFI27 could thus be an effective vention treatment with biologicals. and specific biomarker associated with Sjo¨gren’s Presence of autoantibodies against Ro (SSA) and syndrome [80&]. La (SSB) in serum is commonly used as an accepted criterion for diagnosing Sjo¨gren’s syndrome [37]. Also autoantibodies directed against alpha-phodrin CONCLUSION [70–72] and muscarinic acetylcholine receptors During the last decade, much progress has been [73–75] have been proposed as markers for diagnosis made regarding development and evaluation of and progression of Sjo¨gren’s syndrome. Their role is tools to assess disease progression and disease still not clear as, for example, Potthoff et al. [72] activity in pSS in addition to facilitating pSS diag- showed that neither the severity nor the progression nosis. On the basis of the results described in this of Sjo¨gren’s syndrome correlated with the presence review and our own expertise, we propose the fol- of antialpha-phodrin antibodies in serum. lowing disease progression and disease activity tools Increased serum levels of rheumatoid factor to assess disease activity and progression in pSS. and circulating monoclonal immunoglobulins (in Overall, ESSPRI and ESSDAI are proper instruments particular IgG), reduced levels of C4, and presence of to rate disease activity, to evaluate disease pro- cryoglobulins are frequently observed in Sjo¨gren’s gression, and to assess the effect of treatment in syndrome patients and may be indicative for pSS patients, although some final validation studies patients at risk of developing extraglandular mani- have to be completed before these tools can be festations and lymphomas and thus can be used as a generally applied in pSS. When looking at more monitor to early recognize potential development organ-specific tools, sialometry, sialochemistry, of a lymphoma [5,76–78]. ultrasound, and repeated biopsies are proper tools Regarding the use of serum in rating and under- to assess the salivary gland functioning and regen- standing the effect of intervention treatment with eration. For lacrimal glands, breakup time and tear biologicals, the decrease and re-increase in rheuma- osmolarity are valid, noninvasive tools to assess toid factor, g-globulins, IgG and b2-microglobulin in addition to Schirmer’s test and lisamine green following B-cell depletion therapy with rituximab in staining. Finally, the proteomics and genomics pSS patients might be a useful serum parameter for approaches that are currently in progress may lead assessing treatment effects [18,24&&]. Analysis of to the development of specific tools for the analysis changes in immune activation markers, such as of serum, saliva, and tears in pSS. cytokines involved in lymphocyte activation and inflammation, following rituximab treatment Acknowledgements might be indicative for response to treatment and, None. possibly, for recurrence of disease activity (Pollard et al., unpublished observation). Conflicts of interest Application of unbiased proteomic technologies The authors have obtained funding for their studies in may be useful in further unraveling the mechanisms pSS from National Institutes of Health (proteomics and of autoimmune diseases [79]. As discussed previously, genomics studies; PA-10-067, DE-06-004, R01 first attempts have been made in proteomic and & & DEO19255, U01DE017593-06), Roche (rituximab genomic analysis of saliva [40,41,43 ,44 ,47] and trials), Brystol-Meyers Squib (abatacept trial), and the tears [67] in pSS, but no data are available yet about Dutch Rheumatology Foundation (mechanistic studies). blood samples from pSS patients. However, recently it has been shown that interferon-a (IFN-a)-inducible protein 27 (IFI27) showed the most significant differ- REFERENCES AND RECOMMENDED ence between Sjo¨gren’s syndrome patients and con- READING trols in a DNA microanalysis using a low-density DNA Papers of particular interest, published within the annual period of review, have & been highlighted as: microarray system with 778 genes [80 ]. 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