Emerging treatment for Sjögren’s disease: a review of recent phase II and III trials

Abstract

Introduction:

Sjögren’s Disease, SjD, is a systemic autoimmune disorder characterized by reduced function of the salivary and lacrimal glands. Patients suffer from dryness, fatigue, and pain and may present with or without extra-glandular organ involvement. Symptoms limit SjD patients’ quality of life and are the most difficult to improve with therapy. SjD patients are heterogeneous and clustering them into biologically similar subgroups might improve the efficacy of therapies. The need for therapies that address both the symptoms and extra glandular organ involvement of SjD presents an unmet opportunity that has recently attracted a growing interest in the pharmaceutical industry.

Areas covered:

The goal of this report is to review recent phase II/III studies in SjD. To accomplish our goal, we performed a literature search for phase II/III studies and abstracts recently presented at conferences.

Expert opinion:

This review allows updates the reader on the multitude of recent phase II/III clinical trials. We speculate on how subtypes of SjD will drive future therapeutic targeting and inform pathogenesis.

1. Background

Sjögren’s Disease (SjD) is an autoimmune disease characterized by lymphocytic infiltration of the body’s exocrine glands, including the moisture-producing lacrimal and salivary glands, resulting in hallmark dryness. SjD affects predominantly women (10:1 female to male) with two age peaks: The first peak is in the childbearing age of 20–30 years; the second peak is after menopause when estrogen levels begin to fall, contributing to dryness, and this dryness could make the condition more noticeable [1]. The 2016 criteria for SjD [2] is weighted for clinical and laboratory abnormalities. The diagnosis requires evidence of an immune process as demonstrated by an antibody to SS-A (aka Ro) antigen or a positive salivary gland biopsy. Recent revision has suggested that a positive ultrasound might also have a role in diagnosis, although the criteria have not been updated to reflect this [3].

Symptoms of dryness may accompany other well-recognized autoimmune diseases, such as rheumatoid arthritis (RA), scleroderma, and multiple sclerosis, among others, and are termed associated or overlap SjD. This frequent overlap can make the diagnosis of SjD complex. For example, 50% of patients with dry eye diagnosed as Systemic Lupus Erythematosus (SLE) fulfilled the classification criteria for SjD but not SLE [4,5]. A positive antinuclear antibody (ANA) was associated with an erroneous initial diagnosis. Thus, individuals performing retrospective chart-based analysis might be prone to misclassifying study subjects based on inaccurate diagnostic codes.

Measurement of ocular dryness is done by Schirmer’s test or ocular staining scores. Measurement of dry mouth is usually done by unstimulated saliva flow, which is inaccurate due to swallowed saliva and correlates poorly with patient symptoms [6]. Patient assessment of ocular symptoms of dryness also correlates poorly with objective measurements of the ocular surface [2]. There is a search for appropriate objective surrogate markers for salivary and lacrimal involvement [7–9]. Outside of academic medical centers, oral pathologists are not available to interpret minor salivary gland biopsies, and surgical pathologists might not have the appropriate training to interpret the biopsies correctly.

2. Background for planning pharmaceutic studies

The attention of pharmacologic studies has brought new interest in evaluating SjD. However, several subtle problems are not clearly understood by the rheumatologists or the pharmaceutical community designing new therapies:

1. SjD patients are heterogeneous in their clinical symptoms [10], including at least four subsets:

   1. low symptom burden in all categories (about 10% of patients);
   2. dry with low pain and low fatigue (about 30% of patients);
   3. dry with high pain and low to moderate fatigue (about 23% of patients);
   4. high symptom burden in all categories (about 37% of patients).

   Among these subsets, individuals in the subgroup with low pain and dryness had the greatest objective dryness, rheumatoid factor, and dual anti-SSA (aka anti-Ro) and anti-SSB (aka anti-La) antibody positivity. The highest disease burden group generally had less active SjD yet received more immunosuppressive therapy.

   In contrast, using differing clustering criteria, Tarn et al. [11] found no significant differences in prescription medication use such as hydroxychloroquine, prednisone, or immunosuppressive therapy. Similarly, however, they found clinical features including salivary flow, Schirmer’s test, disease activity, IgG levels, anti-SSA/SSB positivity, and low lymphocytes differed between groups clustered by dryness, fatigue, pain, anxiety, and depression [10] [12]. Here, IFN signatures were highest among individuals with the lowest symptom burden.

   The power of subgrouping by clinical symptoms has been shown in a retrospective analysis of past trials [13]. Future subgrouping into SjD “endotypes” and better surrogate markers for the lacrimal and salivary function are the most promising ways to design future studies [11].

2. Blood and glandular transcriptomes also differentiate subgroups of SjD patients. Patients with a high focus score or lymphoepithelial lesions in their minor or major salivary gland biopsies had gene signatures showing IFNα signaling, IL-12/18 signaling, and T- and B-cell activation. Interestingly, SjD patients with a normal salivary gland biopsy had transcriptomes that were like non-SjD patients [14]. Others have used blood cell subset frequencies or transcriptomes to subgroup SjD patients [15,16]. Interestingly, clustering by blood IFN revealed that low pain was inversely correlated with high IFN levels, similar to past findings [17].

3. The majority of SjD patients do not exhibit extraglandular systemic organ involvement, yet most recent studies exclude SjD patients without moderate/severe extraglandular systemic organ involvement [18]. Longitudinal studies of SjD show that even among patients with extra-glandular features severe enough to qualify for clinical studies, patients have long periods without further extra-glandular involvement, and the repeat salivary gland biopsies show relatively little progression over a ten year period [19,20]. The potential risks of biological agents must be weighed against this relatively benign course for most patients.

   The key unmet need is a significant improvement in symptoms in SjD. Rheumatologists and patients will use the new agents if they improve the patient’s most frequent complaints of fatigue, pain, and brain fog [11]. Although we have improved our understanding of the subsets of this benign subgroup, we have not improved therapy, although some of phase II/III studies reported below are encouraging.

4. The measurement of clinical variables is difficult, and many researchers are not aware that the Sjögren’s Foundation offers online training for clinical evaluations by the Clinical Research Organizations (CROs) that is suitable for food and drug administration (FDA)-approved drugs.

5. Sjögren’s Tool for Assessing Response (STAR) [21] and Composite or Relevant Endpoints for Sjögren’s Syndrome (CRESS) have been proposed. Although consistent across most trials, they gave different results for the same clinical data [22] in 3/9 clinical studies. Adding rheumatoid factor (RF) and salivary gland ultrasound seemed to increase the overall responsiveness of STAR and CRESS.

   Perhaps the most important lesson from the phase II/III studies reviewed here is that it might be easier to achieve improved extraglandular involvement than symptoms including dryness, pain and fatigue. Even within studies that have improved extraglandular organ involvement, symptoms did not improve.

3. Medical need

As noted, there are no FDA-approved disease-modifying therapies for SjD, although topical therapies for dry eyes and several secretagogues have been approved. SjD affects 0.5–2% of the population in the US and Europe [1]. Still, the cost of care is comparable to either RA or SLE [23,24].

The medical costs associated with the treatment of SjD rival those of SLE. The loss in patient productivity due to symptoms of dry eyes and quality of life (QoL) due to fatigue and brain fog range in the billions of dollars each year [25]. Direct costs are related to the value of resources used in diagnosis, treatment, and rehabilitation, and the mean annual direct cost per SjD patient in the UK was calculated as about 90% of RA in 2004, with the difference being the additional surgical interventions in the RA patients [26]. The estimated annual indirect costs include the value of economic productivity, including both labor and the value of economic services such as housework and childcare, exceeding the “costs” of rheumatoid arthritis [27]. Patients with Sjögren’s Disease demonstrate significant absenteeism, productivity impairment, and activity impairment in the workplace. In addition, patients with Sjögren’s Disease demonstrated significantly lower employment rates decreased the number of hours worked and increased work disability claims filed [28]. Finally, gazing at a computer decreases blink rate by almost 90%, exacerbating diminished tear film, diminishing productivity beyond that noted in SLE or RA [29]. The cost of “lost productivity” estimated in the UK alone was over 150 billion pounds [29]. So the costs of productivity due to dryness and fatigue exceed the costs of absenteeism by almost fourfold [30,31].

The utilization of health care resources is like SLE (and shortly behind RA when surgery costs are excluded). Patient satisfaction is less than with these other diseases [31]. In one registry in the UK, the primary cause of a visit to Ophthalmologists or Optometrists in the UK was dry eye syndrome [31].

Patients equate their disability from SjD at a level equivalent to moderate angina-- and would trade two years of life expectancy not to have SjD. The majority of these complaints among SjD are related to dry eye/dry mouth symptoms and fatigue, and “brain fog” [1]. Health-related quality of life (HRQoL) has an increasing role in medical decision-making. HRQoL is markedly reduced in SjD in multiple studies across many countries compared to HRQoL in healthy controls. The reduction in HRQoL is similar to that observed in other chronic diseases such as RA, SLE, and psoriatic arthritis [30]. Impaired HRQoL in SjD is associated with fatigue, pain/articular involvement, ocular and oral involvement, pruritus, sexual dysfunction, impaired sleep, pulmonary manifestations, psychological dysfunction, and impaired physical function.

4. Existing therapies

Treatment for dry eyes usually rests on the frequent use of artificial tears and gels, which are sold over the counter. Topical cyclosporin [32] (Restasis) and lifitegrast drops [33]( inhibits LFA-1) have been approved by the FDA. A combination of topical cyclosporin and 1% diquafosol may be superior to either of these agents [34]. Diquafasol is P2Y2 receptor (purinergic) agonist that promotes tear fluid and mucin secretion and is currently approved in Japan and South Korea for the treatment of the dry eye. Autologous serum may be diluted and used as a topical tear drop in refractory case [35].

Dry mouth therapy consists of gustatory agents, over-the-counter mouth rinses/wetting agents, and frequent trips to dental hygienists for cleaning and fluoride treatments. Pilocarpine and cevimeline are FDA-approved for dry mouth. However, these patients still require high out-of- pocket expenses for dental implants, which have a significantly higher rate of failure [36].

Hydroxychloroquine (HCQ) was used as a routine baseline treatment in SjD patients who exhibited rash, arthritis, myalgia, hyperglobulinemia, and increased ESR (erythrocyte sedimentation rate) [37,38]. In SLE patients, HCQ remains considered as standard “baseline” therapy and is often used as “the usual standard of treatment arm” in SjD trials.” However, the “automatic” use of hydroxychloroquine in SjD is no longer recommended based on a phase III randomized control trial that failed to show symptom improvement with therapy [39,40]. Hydroxychloroquine was originally used in much higher doses, often associated with quinacrine, for treating SjD or SLE [41,42]. However, concern about retinal toxicity at high doses led to the general use of a lower dose, such as 5 mg/kg. Perhaps we should evaluate whether we have dropped the dose of HCQ too low in SjD patients with evidence of arthritis, rash, or elevated ESR in the interests of safety, while unnecessarily exposing SjD patients with only fibromyalgia symptoms to the drug risks.

Primary physicians generally treat fatigue and fibromyalgia symptoms, but they often use amitriptyline or related drugs, whose major side effect is dryness. This may have some benefit on mood but exacerbates the dryness symptoms. One double-blind study has shown the benefit of pregabalin in fibromyalgia-like symptoms [43].

Commonly, methotrexate and mycophenolic acid are used for arthritis, pneumonitis, or extra-glandular organ involvement in combination with HCQ. In patients intolerant of methotrexate, leflunomide is used but has shown limited efficacy [44]. It also has not been approved by the FDA, and its use may be complicated by the patient’s pre-existent leukopenia, hair loss, and gastrointestinal symptoms.

Rituximab is the “go-to” therapy by rheumatologists for extra-glandular organ involvement [45], even though it is not FDA-approved for SjD. In some large studies, fatigue was improved [46] in SjD patients, but this was not confirmed in the two pivotal phase III trials [47,48].

5. Background market review

Thus, the norm in clinical practice is to use rituximab for moderate to severe extra-glandular organ involvement. This presents a quandary for insurance approval, costs to the patient, and potential malpractice liability to the physician for using a drug “off-label.” Ironically, certain insurance companies offer rituximab on their formulary for SjD even though it is not FDA-approved for this indication.

Extraglandular manifestations are treated with rituximab [49] and abatacept [50,51]. In clinical practice, rituximab is frequently used for extraglandular manifestations [52]. There have been conflicting reports on the efficacy of the abatacept [50]. The recent phase II study (ianalumab—a dual action of B-cell depletion and anti-B-cell activating [BAFF] antibody) has invigorated the field of SjD by showing improvement in salivary flow. It may provide clues to the immune-neurological interface mediated by BAFF.

Other novel approaches for the treatment of fatigue, including low-dose IL-2, Fc-RNASE, and brain magnetic stimulation, are also intriguing (studies listed in Table 1).

Table 1.

Summary of Phase II and Phase III Trials in SjD

Study Registration Company	Agent	Phase mechanism	Outcome	Published results on Agent
NCT00001954 Immunex Corporation, a subsidiary of Amgen	Etanercept	Phase II	No significant improvement or ESSPRI	[113]
NCT00632866	Hydroxychloroquine	Phase III	No improvement in ESSPRI	{Gottenberg, 2014 #2407}
NCT01782235 Genentech	Tocilizumab	Phase II Phase III	No significant improvement in ESSDAI or ESSPRI	[114]
NCT00101829 NCT00740948 Roche	Rituximab	Phase III (pivotal trial for FDA approval and not approved)	Did not improve disease activity or symptoms	[47,67,68,115,116]
NCT02631538 GlaxoSmithKline	Rituximab plus Belimumab	Phase II	Improved ESSDAI	[117,118]
NCT01008982 GlaxoSmithKline	Belimumab (BELISS trial)	Phase II	Trend toward improved ESSDAI and ESSPRI	[73,119]
NCT05349214 NCT05350072 Novartis	Ianalumab (VAY736) s.c (NEPTUNUS)	Phase II Anti-BAFF Plus B-cell depletion By Fc modification to enhance NK action	Improved ESSDAI	[76]
NCT02915159 Bristol Myers Squibb	Abatacept (anti-CTLA4)	Phase III	No improvement in ESSDAI or ESSPRI	[82]
NCT04541589 NCT02291029 Novartis	Iscalimab (CFZ533)	Phase II	Improved ESSDAI but not improved ESPRI	[84]
NCT04129164 Viela Bio (acquired by Horizon Therapeutics)	VIB4920 (MEDI4920) Novel Tn3 engineered antagonist of CD40L, so does not activate platelets	Phase II	Improved ESSDAI, fatigue, and physical functioning as reported online	[83]
EudraCT, 2014–003140–12	Leflunomide plus Hydroxychloroquine	Phase II	Improved ESSDAI and trend towards improved ESSPRI
NCT05113004 Assistance Publique - Hôpitaux de Paris	Leflunomide or mycophenolic acid in combination with hydroxychloroquine			[120]
NCT00683345 Swedish Orphan Biovitrum	Anakinra (anti-IL1b)	Phase II	No significant improvement in fatigue	[121]
NCT05383677 AstraZeneca, Saphnelo	Anifrolumab (anti-IFNa type 1R)	Phase II		[122]
NCT03247686 Resolve Therapeutic	RSLV-132 RNAase-Fc (fusion protein)	Phase II	Improved fatigue but no change in ESSDAI. Paradoxical increase in IFN signature proteins	[123]
NCT05016297 Incyte, Eli Lilly	Baricitinib (Jak 2 inhibitor)	Phase II	preliminary (But no posted report of study completed 2020) Initial studies in SLE but then halted	[124]
NCT03100942 Gilead, Gallapagos	Filgotinib (Janus 1 inhibitor) Lanraplenib (spleen kinase inhibitor) Tirabrutinib (Bruton kinase inhibitor)	Phase II	No significant difference in ESSDAI or ESSPRI	[125]
NCT04035668 Novartis	Rembrutinib A irreversible BTK inhibitor	Phase II	Improved ESSDAI and trend toward improvement of unstimulated salivary flow	[100]
NCT04186871 Bristol Myer Squib	Branebrutinib (BMS-986195) An irreversible BTK inhibitor	Phase II		[100,126]
ZymoGenetics, Merck Serono	Atacicept Recombinant fusion protein (TACI-Ig) nonselective binder to BAFF and April)			[127]
NCT04078386 RemeGen Co (China)	TACI (RC 18) (transmembrane activator and CAML interactor); interact with BAFF and April	Phase II	Improved ESSDAI and Improved MI-20
NCT04186871 Bristol-Myers Squibb	Briobacept (BR3- FC) selective BAFF blocker that binds to BAFF but not to APRIL		Animal model	[128]
NCT01552681 Biogen	Baminercept (lymphotoxin beta receptor blocker)	Phase II	No significant improvement in ESSDAI or ESSPRI although block LTBR signaling	[129]
RemGenYantal Rongchang TACI-Fc	Telitacicept (RCT-18)	Phase II	Significant reduction in ESSDAI and improvement in MFI-20 (presented at ACR 2022 but not yet published on-line)	[130]
NCT02334306 Medi5872 Medimmune	ICOSL	Phase II	A small study but improved ESSDAI	[74,86]
NCT04093531 Janssen Pharmaceuticals	Ustekinumab Stelara (anti-IL12/23)	Phase II		[131]
NCT0456319 Eli Lilly	Tibulizumab (BAFF/IL-17) antagonist	Phase II		[131]
NCT04700280 Galapagos	GLPG3970 (salt inducible kinase)	Phase II		[132]
NCT04572841 Sanofi	SAR441344 INX-021 (anti-CD40L)	Phase II
NCT03023592 Toyama Pharmaceutical Toyama Chemical, Taisho	Iguratimod (T-614) An IL-6 inhibitory compound and prevents NFkB activation Approved for treatment of RA in Japan and used in China	Phase II	ESSDAI improved but no improvement ESSPRI	[133]
NCT0270185 Hoffman La Roche	R05459072 Cathepsin inhibitor	Phase II		[134]
NCT03627065 Incyte Incyte Merck	Parsaclisib INCB050465 PI3Kδ(PI3K delta) inhibitor	Phase II	No change in salivary flow ESSDAI and ESSPRI	[132]
NCT02435173 Novartis	Leniolisib (CDZ173) Seletalisib PI3Kδ(PI3K delta) inhibitor	Phase II	Negative or with a trend toward improved ESSPRI/ESSDAI and rash side effect	[135,136]
NCT02610543 UCB Pharma	UCB5857			[137]
NCT04968912 Janssen Research & Development, LLC	Nipocalimab MoAb to Block	Phase II
	endogenous neonatal receptor (FcRn)
NCT02691377 Guang’anmen Hospital of China Academy of Chinese Medical Sciences	Accupuncture
NCT04119128 Federal University of São Paulo	Direct Cranial Nerve Stimulation	Phase II	Improvement in fatigue	[138]
NCT01693393 Charite University, Berlin, Germany	Low dose cyclospororin A	Phase II	Improvement in ESSDAI	[139]
NCT05605665 Investigator sponsored Peking Union Medical Hospital	Low dose IL-2	Phase II	Improvement in ESSDAI and fatigue	[140,141]
NCT04988087 Novartis	MHV370 (Toll signaling)	Phase II
NCT02472795 Idorsia Pharmaceuticals Ltd.	Cenerimod (S1PR1 modulator) Which alters lymphocyte re- circulation	Phase II	No results reports	[142]
NCT03926286 Investigator sponsored University of Miami	Fecal Transplant	Phase II	No results in humans; promising in rodents	[143]

6. Current research goals

In SjD, the extraglandular manifestations are measured by a weighted scale called the ESSDAI (EULAR [European Alliance of Associations for Rheumatology] Sjögren Syndrome Disease Activity Index), and a clinically significant improvement is considered ≥3 units. The ESSDAI can theoretically range from 1–131, but most patients with dry eyes/dry mouth have an ESSDAI of about two and those with systemic involvement typically have an ESSDAI from five to 13, so a population with an ESSDAI of five or more (moderate/active disease activity) is usually required for inclusion in the study [53].

It will be important to identify markers of SjD subgroups that predict flares so that that subset can be followed more carefully and therapy started promptly.

The secondary research goal is to improve the symptoms of dryness of eyes and mouth, as well as constitutional symptoms of fatigue, and pain currently measured by EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI).

Although no single gene has been associated with fatigue in SjD patients [54], transcriptional analysis of the high fatigue subset has suggested that at least 19 different pathways show alteration in the “high fatigue” subset of SjD patients (including 55 different genes). The IFN1 signature, although elevated in SjD patients with extraglandular symptoms, was not correlated with fatigue [54]. Further insight into the pathogenesis driving major SjD symptoms is a major need in SjD research.

7. Scientific rationale

It has been presumed that T-cells and B-cells infiltrating the gland release inflammatory cytokines, free oxygen radicals, and metalloproteinases that destroy or interfere with the neural innervation/water transport in glandular cells [55,56].

Interestingly, there is very poor correlation between the patient’s symptoms (dry mouth or dry eyes) and the objective examination of the patient. Stern et al. [57,58] have proposed a “functional circuit” involving the communication between the afferent nerves of lacrimal and salivary glands and the thalamic region of the brain, where specific neuromodulators modify pain thresholds [51–53]. Reducing the inflammation in glandular tissue may reduce the neural signals transmitted to the thalamic areas of the Vth cranial nerve and onto the thalamus.

Given the promising phase II results discussed below, we hope that the improvement in disease activity (ESSDAI) and hallmark symptoms (ESSPRI) will occur in larger phase III studies.

However, the lack of improvement of symptoms even when objective disease activity improves, along with the poor correlation of symptoms with objective findings, suggests that we have to look further into how the immune system affects the central nervous response to pain, fatigue, and dryness.

The success calcitonin group related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP) to treat migraines, that lack traditional inflammatory markers [59], indicates symptoms like pain might be tied to neurologic signaling pathways. Similarly, myasthenia gravis may have flares without elevation of traditional inflammatory markers and show improvement with IVIG or blockers of the neonatal Fc receptor [60].

8. Competitive environment: A review of drugs in phase II/III

Previous Trials

Initial trials with tumor necrosis factor (TNF) were reported as positive, although the studies were not repeatable, and the original manuscript was retracted [61–63]. TNF and IL-6 inhibitors such as infliximab, etanercept, and tocilizumab did not add either significant improvement in disease activity (ESSDAI) or symptoms (ESSPRI) (Table 1). This was disappointing since most infiltrating lymphocytes in the salivary glands or extraglandular tissues were T-cells [64,65].

9. Recent Phase IIa/IIb Trials

Leflunomide and hydroxychloroquine (HCQ)

Leflunomide and HCQ are well known in the rheumatology community. A recent study combining both of these drugs (registered as EudraCT, 2013–003140-12) was done between 2016 and 2017 and published in 2020 [66].

This phase IIA randomized trial studied 29 patients with an ESSDAI of >5 and salivary gland biopsy with a focus score >1. Participants were randomized (2:1) to receive leflunomide 20 mg/day and hydroxychloroquine 400 mg/day. While they noted improvement in the ESSDAI of 4.35 in the treated group compared to the placebo, there was no reported improvement in the ESSPRI.

Although this trial used medications approved for RA (and now available as generics), it should be noted that the number of patients in each arm was extremely small, and no further studies have been reported (or registered) in the last five years.

Rituximab

Rituximab is an anti-CD20 monoclonal antibody that targets and depletes B cells. Although the FDA has not approved rituximab for SjD, it is still the most widely used biologic by rheumatologists for treating extraglandular organ involvement. A summary of the value of rituximab treatment in SjD was presented by Verstappen et al. in 2017 [67]. Although rituximab did not improve dryness, fatigue, or brain fog in the majority of patients (see below), many well-designed single- and multi-center double-blind trials showed efficacy in extraglandular symptoms (reviewed in [67]), and these observations still set the standard by which rheumatologists evaluate other therapies.

TRACTISS was a UK multi-center, double-blind, randomized, controlled trial of 133 patients with high symptom burden, recent onset disease, or high disease activity. Participants were randomized 1:1 to receive two courses of rituximab or placebo infusion in addition to standardized therapy (Trial registration UKCRN 9809 ISRCTN65360827). This study did not show improvement in symptoms or disease activity with rituximab [68].

TEARS was a phase II/III trial that did not show significant ESSDAI improvement in patients with extraglandular organ involvement (high ESSDAI). Still, the SjD patients did not achieve the endpoint of 30% improvement in at least two of four visual analogue scores (VAS) for global disease, pain, fatigue, or dryness at week 24 [47,69].

A meta-analysis of 32 trials evaluating rituximab therapy was reviewed. Twenty-two trials examined ocular and oral dryness, for which only two and four trials showed statistically significant symptomatic improvement [70]. No studies found a benefit for tear production, and 3/16 found a slight improvement in salivary flow.

A common misconception is that the only action of rituximab is B-cell depletion. However, the clinical response of rituximab appears to correlate with the depletion of memory cells (including CD19+ and CD27+) more than the extent of depletion of CD20+ B-cells [71]. Furthermore, rituximab might restore T-cell subset abnormalities, including numbers of T regulatory cells [72].

Naïve B-cells expressing CD38 repopulate the periphery from the bone marrow, perhaps in response to increased BAFF levels. In the absence of circulation of autoreactive B-cells, a significant reduction of CD4+ T-cells occurs and alteration of CD8+ T-cells, probably due to the reduction of IL-17 [72].

Belimumab

Belimumab is an anti-BAFF biologic therapy that targets B-cell pathways in SjD. Among 30 SjD patients enrolled in a 1-year open-label trial, all received belimumab 10mg/kg at weeks 0.2 and 4 weeks, then every 4 weeks [73]. The results from the open-label were encouraging, and a phase III randomized study was suggested based on its safety profile.

However, instead of a phase III study of belimumab versus placebo, a study of belimumab as a sequential therapy after rituximab was undertaken (discussed below), and the results of belimumab only were assessed in one arm of this study [74]

Sequential belimumab and rituximab [49]

In a 68-week phase II study, 86 patients were randomized to one of four arms: placebo, s.c belimumab, I.V. rituximab, or sequential belimumab plus rituximab. Rituximab (1 gm), belimumab 200 mg s.c every two weeks. Near complete depletion of the minor salivary gland, CD20+ B-cells were noted only in the belimumab plus rituximab. The ESSDAI decreased by 5.7 units in the rituximab plus belimumab group [49], A decrease in ESSDAI in the belimumab-only group was 3.9, and rituximab-only of 4.4, compared to a decrease of 1.8 in the placebo group [49].

Using the CRESS outcome method at week 68, they found 35.3% were classified responders in the combined rituximab plus belimumab, 36.8% in the belimumab only, and 18.8% in the rituximab-only group. The loading dose steroid was not discussed. The combined treatment group also showed a trend for improvement in stimulated saliva flow, but no improvement in patient-reported symptoms of oral dryness.

Ianalumab (Vay 736)

Ianalumab is a dual mode of action monoclonal antibody combining BAFF receptor inhibition with B-cell depletion. The humanized antibody has anti-BAFF receptor activity but has a fucosylated Fc receptor to enhance NK cell depletion of B-cells. (Disclosure: The authors are consultants to Novartis and an author of publications about this agent.)

A controlled dose-ranging phase IIb study involving 190 patients randomized to different doses was initially presented at the European Union League Against Rheumatism (EULAR) in 2020 by Dorner et al. [75], and a subsequent manuscript with the 24-week follow-up data was published [76]. The results of the 52-week follow-up, including a repeat dosing at 24 weeks, were presented in abstract form at EULAR by Dorner et al. [77]. The 52-week results showed that a 300 mg subcutaneous ianalumab maintained the improved ESSDAI (primary outcome), ESSPRI (secondary outcome), improved tear/saliva flow, and decreased fatigue using SF-36 (Short Form 36 of multidimensional Fatigue inventory). Also, the patient and physician global assessments both improved. It should be noted that each dosing was proceeded by premedication of solumedrol 250 mg intravenously. This high dose of corticosteroids might have contributed to the relatively high response rate in the placebo group.

Of particular interest to the author, several dosing regimens were compared. The ianalumab (VAY736) was used at 150 mg with the same level of B-cell depletion as the 300 mg dose. However, the 300 mg dose also was sufficient to block the BAFF receptor, while the 150 mg dose did not achieve complete blockade. This demonstrates that B-cell depletion may be necessary (but not sufficient) to allow improvement in QoL assessments and is potentially an important insight into the linkage between the immune and neuroimmune (fatigue and secretory) aspects of SjD.

Telitacicept

Telitacicept is a fully humanized transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI)-Fc that targets BAFF and a proliferation-inducing ligand (APRIL) [78]. APRIL and BAFF have receptors present on B-cells, targeting B-cells in SjD.

In a phase II trial, 42 Chinese patients were assigned in a 1:1:1 ratio to receive weekly subcutaneous telitacicept 240 mg, 160 mg, or placebo for 24 wks. The primary endpoint was a change from baseline ESSDAI. Administration of telitacicept 240 mg resulted in a significant reduction in ESSDAI score. It improved MFI-20 (p>.05) compared to the placebo (results reported at ACR meeting 2022 [79].

Also, a marked B-cell depletion was noted at both doses. They also reported a significantly greater reduction in the MFI20 (0<.05). Significant reductions in serum IgG levels were noted, but no serious adverse events were noted in the teitacicept group.

Although exciting, a much larger cohort and multinational study will be required to assess the safety and efficacy of SjD.

Telitacept was approved for use in SLE in China [80]. A recent abstract by Zhang et al. [80] reported significant B-cell depletions with an increase in B-reg cells and a relative decrease in B-cell memory cells.

Abatacept

This molecule targets CD80/86 co-stimulation, blocking the interaction between T-cells and antigen presenting cells. A phase II study of SjD and open label phase III study were promising, but larger phase III trials did not confirm these initial results [81,82]. In the phase III randomized placebo controlled trial, abatacept failed to improve ESSPRI, ESSDAI, or stimulated salivary flow. Abatacept did improve some disease related laboratory measurements such as IgA, IgG, IgM, and RF [82].

CFZ533 (Iscalimab)

CFZ533, a fully human antagonist anti-CD40 monoclonal IgG1 antibody, contains a modified Fc domain that renders it unable to mediate Fcγ-dependent effector functions [83].

In the double-blind phase of the trial, patients were randomly assigned (2:1) via computer-generated unique randomization numbers to receive subcutaneous iscalimab (3 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 1) or intravenous iscalimab (10 mg/kg), or placebo at weeks 0, 2, 4, and 8 (cohort 2). The intravenous dose group significantly improved ESSDAI, while the subcutaneous group did not [84].

Phase II trials involving 82 patients showed a significant improvement in ESSDAI and a trend toward improvement of ESSPRI.

Several modified anti-CD40 antagonists have been developed, but only CFZ533 has been reported in SjD trials [83].

VIB4920 -- a novel inhibitor of CD40L

This CD40L-targeting protein has been genetically engineered to lack the Fc portion of the molecule implicated in thromboembolic events that led to the cessation of clinical trials of inhibitors of CD40L many years ago.

CD40L is predominantly expressed in T-cells and the CD40-CD40L interaction and is critical for the formation of germinal centers. CD40L is also found on platelets and many other target tissues, including vascular endothelial cells [83]. Early trials to target the CD40L showed evidence of good therapeutic potential but were complicated by thromboembolic events [83] in three patients in two successive trials.

One potential explanation for the unanticipated safety issues in clinical trials is linked to the expression pattern of FcγRIIa (or CD32a), which is found on human, but not mouse, platelets. CD40L is highly upregulated on activated platelets, and concurrent antibody-mediated binding to CD40L and FcγRIIa on adjacent platelets is believed to lead to platelet aggregation resulting in thrombosis. Importantly, the Fc portion of the anti-CD40L mAB has been definitively linked with its toxicity, where immune complexes (ICs) comprised of anti-CD40L antibody and recombinant CD40L, activate platelets in vitro, in a FcγRIIa-dependent manner. On the Horizon website, preliminary results stated that both primary and secondary endpoints (ESSDAI and ESSPRI) were reached. Still, these results have not been published and thus have not gone through peer review. This website notes that the compound is scheduled for phase III trials. Other anti-CD40L are under development and might show promise in treating SjD.

Medi5872 (AMG 557)—An ICOS ligand

The inducible T-cell costimulatory (ICOS) pathway supports CD4+ T follicular helper cell differentiation and promotes germinal center formation [85] A fully humanized anti-ICOS ligand was used in a phase II study of SjD patients [74,86]. In a small cohort of 32 patients, the drug had a good safety record and had a nonsignificant trend toward improved ESSDAI, but not ESSPRI.

RSLV-132

RSLV-132 is an RNase fused to the Fc region of human IgG1[87]. It is designed to digest extracellular RNA, presumably reducing downstream Toll-like receptor (TLR) activity resulting in interferon activity. Thirty patients were randomized to receive an intravenous placebo or drug (10 mg/k) every two weeks. The treated patients were found to have clinically meaningful improvements improvement in four different measures of fatigue: ESSPRI, Functional Assessment of Chronic Illness Therapy (FACIT-F), Profile of Fatigue (ProF), and Digit Symbol Substitution Test (DSST) at day 99, in comparison to placebo-treated patients. Although there was a significant improvement in fatigue, the study did not meet the secondary goal of significant improvement in ESSDAI. This might be explained by the inclusion criteria that did not require a high ESSDAI. Indeed, fewer than half of subjects included in the study had an ESSDAI of at least five.

The study was based on the hypothesis that circulating Y-RNAs in extracellular vesicles and ribonucleoprotein complexes proteins would stimulate Toll-like receptors or other pattern-recognition receptors (PAMP) and respond with a robust action of the innate immune system [88]. This process would simulate the fatigue induced by the RNA virus infections [89].

However, this study had the paradoxical result of upregulated IFN inducible genes. This study and the preceding study on anifrolumab (anti-IFN receptor), which decreased IFN signature, but did not affect ESSDAI or ESSPRI, points out the “double-edge sword of IFN.” We have based a great deal of research on the pivotal role of IFN in the pathogenesis of SjD. On the other hand, administering interferon a2 lozenges underwent trials to improve saliva production and showed mild increased salivary flow (but not clinical improvement of dryness).

However, the role of IFNa and the multiple subtypes of IFN on various organs still needs to be better understood [90]. Taken together with the anifrolumab study, one explanation is that small RNAs may be able to cross the blood-brain barrier and have certain effects on fatigue. In contrast, the same RNAs may have a completely different effect when they act through TLR receptors. Other forms and sources of RNA, such as IFN-induced protein kinase RNA in chronic fatigue syndrome, might also contribute to the IFN-RNA-fatigue axis.

Low-Dose Interleukin 2 (LD-LD IL-2) [91]

Low dose IL-2 increases numbers of T regulatory (Treg) cells and can inhibit T follicular helper and Th17 cell differentiation [92,93]. 60 SjD patients were recruited, with 30 receiving low-dose IL-2. The patients received recombinant human IL-2Ala (Beijing SL Pharma) to a dose of 1 million IU subcutaneously every other day for two weeks, followed by a 2-week break. There were treatment cycles followed by a 12-week observational period. Laboratory examination showed increased Treg and Breg cells (CD24 hi and CD27 +) [91,94].

ESSDAI improvement of more than three units was achieved in 66% of the LD-LDIL-2 patients compared to 26% in the placebo group. There was a greater resolution of dryness, pain, and fatigue in the treated group (p<.01). These improvements occurred in ESSPRI, pain VAS and fatigue VAS, MFI-20, and SF-36 measurements. The STAR evaluation measured the treatment response [91].

A review of this therapy in other rheumatic disorders has shown a high incidence of local skin reactions, which were not seen in this study [95]. Although high-dose IL-2 has been approved in metastatic disease, low-dose IL-2 has been consistently shown to alter Treg and Breg, but there are only scattered case reports on its use outside of China [95].

Bruton Tyrosine Kinase Inhibitors

Bruton’s tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase expressed in several types of cells of hematopoietic origin, which participate in both innate and adaptive immunity [96]. Functionally, BTK is an essential intracellular signaling molecule in the development, survival, and activation of B-cells. It was first identified as the genetic defect in the primary immunodeficiency X-linked agammaglobulinemia, characterized by an almost complete loss of serum immunoglobulins and circulating mature B-cells, with a subsequent susceptibility to infections [97].

BTK is involved in various B-cell functions, including antigen presentation and production of antibodies by B-cell antigen receptor (BCR) signaling. In addition, BTK is important in the normal functioning of several immune cells. It is also involved in activating innate immune cells (macrophages, neutrophils, and mast cells/basophils) by immune complexes. BTK controls cytokine production, phagocytosis, and the production of inflammatory mediators [98]. Furthermore, BTK is involved in platelet activation via the glycoprotein VI receptor [99] and osteoclast differentiation via the receptor activator of NF-kB.

A potential issue with BTK inhibitors concerns the lack of selectivity and associated toxicity profiles of first-generation BTK candidates when used in the long-term treatment of immune-mediated diseases [100]. Second-generation BTK inhibitors have made great strides in limiting off-target activities for distantly related kinases. However, they have had variable success at limiting cross-reactivity within the more closely related TEC family of kinases. (The Tec family is a recently emerging subfamily of non-receptor protein-tyrosine kinases represented by its first member, Tec.) This family comprises five members, namely Tec, Btk, Itk/Emt/Tsk, Bmx, and Txk/Rlk) [100].

Remibrutanib (Lou 064) was studied in phase II placebo-controlled study with moderate to severe SjD patients. 73 patients were randomized to receive Remibrutanib 10 mg BID (n=24), 100 mg QD (n=25) or placebo (n=24). ESSDAI improved significantly, and there was a trend of improved unstimulated saliva flow. This study presented at the ACR (13S130 in Philadelphia), but has yet to be published online, extends the previous phase I trial that examined the safety and pharmacokinetics [101].

Inhibition of interferon alfa (Anifrolumab)

Anifrolumab is an antagonist to the IFNa type 1 receptor (anti-IFNa type 1Rand is currently under study for the treatment of SjD (ANISE-II study). However, the drug has been studied (and approved by the FDA) for use in SLE. In a meta-analysis of the Tulip 1 and Tulip 2 trials of Anifrolumab in the SLE [102], SLE patients’ constitutional symptoms showed improvement only in the subgroup with improved BICLA scores (mostly skin improvement). In the non-BICLA response subgroup, there was no improvement in multiple measures of fatigue and QoL. The Anifrolumab inhibited the interferon signature in both groups. IFN related genes can be categorized into modules or signatures to generate disease-specific fingerprints that represent type 1 and type 2 IFN activity [103].

The results of Bodewes et al [17,104] showed that IFN-positive patients are not more fatigued than IFN-negative patients and have better QoL (before and after treatment), linked to a decrease in fatigue [105]. This challenges our normal assumption that stimulation of the innate or acquired immune system would lead to Toll receptor activation and IFNa release.

However, we may see a later phase of this process when we see fatigued SjD patients long after their acute “viral” response [106] when the immune system is trying to downregulate the IFNa response. This paradoxical inverse correlation between IFN signature intensive and QoL are in line with older studies [106] in which inflammatory parameters were uncoupled from fatigue. This may be due to the induction by IFNa of cytosolic receptors (like Rig1 and Tank 1) that attempt to down-regulate immune responses to RNA or DNA viruses [105].

Nipocalimab

Nipocalimab is a fully human, effectless IgG1 anti-neonatal Fc receptor (FcRn) monoclonal antibody that prevents IgG recycling. This results in a sustained lowering of IgG. A poster at the recent ACR suggested that this agent significantly lowered ESSDAI (#1854, still needs to be published). This agent has been used in trials of Myasthenia Gravis and is now entering phase III. Another neonatal receptor has been approved for Myasthenia, showing impressive results in IVIG refractory ITP, and is currently in trial for POTS disease. The beauty of a neonatal receptor blocker is that one does not need to know the antibody being removed. Still, there seems to be a preferential removal of antibodies that are included in immune complexes, which gives specificity to autoimmune therapy.

RO5459072 (a cathepsin S inhibitor)

The cysteine protease cathepsin S (CatS) is crucially involved in MHCII processing and T-cell stimulation, and elevated levels have been found in patients with SjD. CatS activity was significantly elevated in tear fluid, but no other compartments were inversely associated with exocrine function in SjD patients and could significantly be suppressed by RO5459072.

Amongst the lysosomal cysteine cathepsin family of proteases, cathepsin-S (CTSS) holds particular interest due to distinctive properties, including a normally restricted expression profile, inducible upregulation, and activity at a broad pH range. Consequently, while CTSS is well-established as a member of the proteolytic cocktail within the lysosome degrading unwanted and damaged proteins, it has increasingly been shown to mediate several distinct, more selective roles, including antigen processing and antigen presentation and cleavage of substrates both intra and extracellular.

A recent randomized, double-blind, placebo-controlled phase II study in 65 SjD patients did not show improvement in the primary outcome of ESSDAI score. There was a nonsignificant decrease in circulating B- and T-cells in the RO5459072 group [107].

10. Potential development issues

In achieving an improved ESSDAI, most candidate drugs have depleted B-cells, and the risk for infection remains to be determined. For example, patients treated with rituximab were found to be more likely to have severe outcomes with Covid infection [108]. The possibility that the immune system will not detect some viral infections due to the “immuno- compromise” induced by the drugs is always a worrisome possibility.

The impact of these agents on BAFF and its ligands on both immunization and opportunistic infections cannot be accurately predicted in the short time of phase II development.

The interaction of these agents with common (and uncommonly) used drugs for other conditions will not become apparent until long after phase II/III studies. Thus, these drugs may inadvertently interact with drugs important for diabetes, lipid control, or hypertension.

The immune system provides surveillance against tumors as well as bacteria and may be compromised, and long-term follow-up will be required to determine if relapses of prior tumors or newly emergent tumors are associated.

11. Conclusion

SjD is a chronic, autoimmune condition characterized by lymphocytic infiltration of the exocrine glands and B-cell dysfunction. There are no proven treatments that alter disease progression or treat the constitutional manifestations of the disease.

B-cell depletion is used in patients with extraglandular manifestations, but its overall impact on constitutional symptoms (fatigue, pain, brain fog) has NOT been demonstrated in most studies. Most of the phase II/III trial data has been relatively disappointing, but at least some agents have shown promise.

Ianalumab (a bi-specific anti-BAFF monoclonal) showed improvement in constitutional symptoms and has advanced into phase III in a subcutaneous formulation. It will be important to see if the premedication (solumedrol 250 mg) before administration played a role in the results, as the planned phase III will not have this steroid.

Several “proof of concept” studies involving small numbers of patients were presented.

Low-dose IL-2 was reported to have dramatic effects on extraglandular and constitutional effects in a study conducted in China. However, the number of patients was small (only 60 patients in the entire cohort before randomization). The study was completed in 2019 and recently reported. No phase III follow-up was listed on clinicaltrials.gov, but this may reflect the influence of Covid in China on clinical studies.

Telitacicept is a fully human TACI-Fc fusion protein that targets B-lymphocyte stimulator (BLyS), and A-Proliferating-Inducing Ligand (APRIL) in SjD was also reported from China. The study was reported in an abstract at the ACR 2022 but not yet published online. However, among the cohort of 42 patients, the group receiving the highest dose (probably 13 patients) was reported to have an impressive improvement in both ESSDAI and MI-20 scores. No phase III trials have been posted.

RSLV-132 is a novel RNase1-Fc fusion protein designed to remove RNA and was successful in improving fatigue in a small cohort of 42 patients. RSLV-132 was not effective in improving ESSDAI. Interestingly, the IFNa signature proteins increased during treatment. A previous small trial in SLE showed positive results with 42 patients with moderately active disease. New data demonstrate that SjD patients fall into distinct clinically defined subgroups.

It is increasingly clear that clinical trials in SjD will require patient stratification, as well as relevant and sensitive outcome measures.

Thus, the seemingly disappointing phase II trials might be more successful for the individual patient under consideration if a proper stratification can be found to match the patient to treatment.

12. Expert Opinion

SjD therapy represents a set of conflicting goals. Most patients have fibromyalgia-like constitutional symptoms-- and are desperate for relief. This is a group of patients that are losing their quality of life and would choose any therapy for relief.

Some SjD patients have intermittent flares of extra glandular organ involvement that frequently respond to an inexpensive therapy like rituximab—but this therapy does not improve their constitutional symptoms and quality of life. Thus, one challenge is to find a therapy (or a mechanism of stratification) that exposes only patients at risk for extraglandular organ involvement. A further challenge is to find a therapy for patients with only “benign” constitution symptoms with an acceptable risk profile.

By choosing a primary endpoint of a significant reduction of ESSDAI, the cohort must have an elevated ESSDAI at the enrollment stage. Thus, we do not know how treatments studied in high ESSDAI patients will compare to the drug’s response in most low ESSDAI patients.

The observation that symptoms stratify patients -- and that each subgroup has an overlapping profile of transcription products means that we have not yet found an adequate “surrogate” marker for rapidly screening patients to a particular therapy, like the strategy of directed therapy which has been so successful in treating cancers.

Perhaps it is time to re-think our strategy and admit that we have become hostages of our pathogenetic theories of pathogenesis. Although these theories work well to explain systemic extraglandular organ involvement, they do not explain the constitutional symptoms.

The symptoms of fatigue may be more closely related to neural or vascular regulation, as demonstrated by the presence of anti-muscarinic M3 receptor antibodies in SjD demonstrated by adoptive transfer experiments [109].

Since the offending antibodies in SjD might vary from patient to patient, we will await the results of antibodies to neonatal Fc receptors, which have been so effective in treating myasthenia gravis, pemphigus Vulgaris, and ITP refractory to IV-Ig [110,111]. The beauty of this approach is that you do not need to know the identity of the autoantibody to remove it. Presumably, pathogenetic antibodies (i.e., forming immune complexes) will be selectively eliminated [112].

In concentrating exclusively on cytokine networks linked to extraglandular organ involvement, we still need to examine the role of antibodies that regulate cerebral blood flow and G-coupled receptors and other antibodies directly tied to extraglandular organ involvement symptoms.