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What is new in Sjögren’s Syndrome (EULAR 2013)

Hendrika Bootsma (The Netherlands) at EULAR 2013 Madrid, June 14.

Diagnosis / classification criteria

2013-06-15 11.44.27Criteria must be clear, easy to apply and specific. “The previous AECG classification criteria for Sjögren’s syndrome had been criticized for including subjective tests (symptoms of oral and ocular dryness), physiologic measures that lack specificity, and objective tests that are not diagnostically equivalent. Therefore, the Sjögren’s International Collaborative Clinical Alliance Research Groups proposed an alternative criteria set composed of only objective measures (including lip biopsy). The level of agreement between the preliminary American College of Rheumatology (ACR) criteria and the AECG criteria was high when all objective tests were available to define the AECG criteria but low when subjective tests were allowed to replace the objective tests.” (Bootsma, H., Spijkervet, F. K. L., Kroese, F. G. M. and Vissink, A. (2013), Toward new classification criteria for Sjögren’s syndrome?. Arthritis & Rheumatism, 65: 21–23. doi: 10.1002/art.37701) 

Proposed classification criteria for Sjögren’s syndrome ( Sjögren’s International Collaborative Clinical Alliance (SICCA) Research Groups)
Arthritis Care Res (Hoboken). 2012 April; 64(4): 475–487

The classification of Sjögren’s syndrome, which applies to individuals with signs/symptoms that may be suggestive of SS, will be met in patients who have at least two of the following three objective features:

  1. Positive serum anti-SSA (Ro) and/or anti-SSB (La) or [positive rheumatoid factor and ANA ≥ 1:320]
  2. Labial salivary gland biopsy exhibiting focal lymphocytic sialadenitis2 with a focus score ≥ 1 focus / 4 mm2
  3. Keratoconjunctivitis sicca with ocular staining score ≥ 3 (assuming that individual is not currently using daily eye drops for glaucoma, and has not had corneal surgery or cosmetic eyelid surgery in the last 5 years) 3
Prior diagnosis of any of the following conditions would exclude participation in Sjögren’s syndrome studies or therapeutic trials because of overlapping clinical features or interference with criteria tests:

  • History of head and neck radiation treatment
  • Hepatitis C infection
  • Acquired Immunodeficiency Syndrome
  • Sarcoidosis
  • Amyloidosis
  • Graft versus host disease
  • IgG4-related disease
1We excluded participants with rheumatoid arthritis, systemic lupus, scleroderma, or other connective tissue disease from these analyses since there were only 87 (6%) such participants.
2Using histopathological definitions and focus score assessment methods previously described
3Using ocular staining score previously described. Sodium fluorescein is considered the premier dye for corneal staining and, similarly, rose bengal for conjunctival staining. Ocular staining score is the sum of a 0–6 score for fluorescein staining of the cornea and a 0–3 score for lissamine green staining of both nasal and temporal bulbar conjunctivae, yielding a total score ranging from 0 to 12.. Performance of a new staining score is currently being compared to Schirmer test.

These proposed new AECG classification criteria for Sjögren’s syndrome (published in 2012) show 92% sensitivity, 95% specificity and -like the ACR criteria- now only contain objective parameters, subjective items are no longer included.

Bootsma: “Adding ultrasonography of salivary glands may further increase the sensitivity of the current criteria set. Also salivary glands ultrasonography might enable early detection of lymphoma and possibly be of help to monitor disease activity / treatment efficacy”. (Bootsma, H., Spijkervet, F. K. L., Kroese, F. G. M. and Vissink, A. (2013), Toward new classification criteria for Sjögren’s syndrome?. Arthritis & Rheumatism, 65: 21–23. doi: 10.1002/art.37701).

Bootsma: “Challenge remains to identify early Sjöogren’s Syndrome in order to enter the early treatment window of opportunity”.

Disease Activity Assessment

ESSDAI: EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI).physician recorded index that covers 12 domains. The maximum theoretical ESSDAI score is 123, but in general, even in active disease the scores are generally in a much lower range with scores of approximately 50 on the upper side of the clinical spectrum.
ESSPRI: EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) patient recorded, easy tot use index not only in trials but also in daily clinical practice. The ESSPRI is a very short questionnaire to be completed by the patient and it contains just three items to be given an activity level score between 0-10: pain, fatigue and dryness, the final ESSPRI score is the mean of all three scores and therefore also between 0-10.

Both ESSDAI and ESSPRI are sensitive to measure change. But there is a low correlation between both indices, i.e. they measure different aspects, both are clinically relevant however.
1. Raphaèle Seror, Hendrika Bootsma, Simon J. Bowman, Thomas Dörner, Jacques-Eric Gottenberg, Xavier Mariette, Manel Ramos-Casals, Philippe Ravaud, Elke Theander, Athanasios Tzioufas, Claudio Vitali, Outcome measures for primary Sjögren’s syndrome, Journal of Autoimmunity, >Volume 39, Issues 1–2, August 2012, Pages 97-102
2. Seror R, Gottenberg JE, Devauchelle-Pensec V, Dubost JJ, Le Guern V, Hayem G, Fauchais AL, Goeb V, Hachulla E, Hatron PY, Larroche C, Morel J, Pedriger A, Puéchal X, Rist S, Saraux A, Sene D, Sibilia J, Vittecoq O, Zarnitsky C, Labetoulle M, Ravaud P, Mariette X.ESSDAI and ESSPRI: EULAR indexes for a complete picture of primary Sjögren’s syndrome patients.
Arthritis Care Res (Hoboken). 2013 Feb 22. doi: 10.1002/acr.21991. [Epub ahead of

The ESSDAI and ESSPRI are from now on used as disease activity parameters in (upcoming) trials, e.g. the abatacept open label study presented at EUAR 2013 (OP0112 ) included impressive decrease in both indices after 24 weeks of treatment.

Burden of the disease
Impaired functional status (see also the abstract presented by Bossema et al. (THU0581-PHR) “Spousal protective buffering is related to a lower physical and mental quality of life in patients with Sjögren’ssydnrome”)
-Symptoms of dysautonomia

Thus far there is no single medication available that has been proven to be effective in Sjögren’s Sydnrome in randomised control trials (RCTs). Treatment at this moment is therefore symptomatic, supportive and empiric. In a subset of patients, in which arthralgia is a major symptom some clinicians prescribe antimalarials (hydroxychloroquin) for Sjögren’s syndrome patients with mixed (subjective) results. A recent large (n=120 patients) study has been conducted to see whether hydroxychloroquin is an effective agent in Sjögren’s syndrome. The study, presented during this EULAR 2013 meeting (OP0114) after 12 months follow-up confirmed previous results of a study in 1993 by Kruize et al.: hydroxychloroquin is not superior to placebo, so there is no real proof of it’s efficacy in this condition.

More recently biologicals are studied for their potential efficacy in (early) Sjögren’ssyndrome. Proper patient selection (detecting early stages of diseae) is important here. B-cell targeting with either rituximab or belimumab has been studied, and a study with epratizumab is planned for the near future.

In Groningen, the Netrherlands, rituximab ahs been studied in primary Sjögren’s Syndrome before. The conclusion was disappointing at 24 weeks after promising results at 6 weeks: no improvement of the predefined primary endpoint (salivary flow) was found, however significant decrease of ESSDAI scores was noted, especially in patients with accompanied vasculitis signs. So far this remains the only study to show effect on systemic signs and symptoms in Sjögren’s Syndrome and this has not yet been reproduced by other research grtoups. However the negative clinical response was in contrast with observed histopathological response that was present at tissue level. It is hypothetised that possibly patient selection had included too much patients with progressed rather then early (enough) disease to measure clinical benefit. Although the research group in Groningen presented new promising data in which not the B-cells but the T-cells are targeted (see below), the group still sees potential roles for both B-cell and T-cell targeted approaches in Sjögren’s Syndrome. Both require further studies of efficacy and safety.

Apart from rituximab also belimumab, registered for the treatment of SLE, has been studied in Sjögren’s Syndrome.

Seror et al. from the group of Xavier Mariette of France presented their work during this meeting (OP0113) and treated 30 primary Sjögren’s Syndrome patients with belimumab with the same dosage regimen as is used in lupus patients. They found that 19/30 patients (63%) achieved the primary end-point which was a composite clinico-biological outcome. Also a significant decrease of both ESSDAI/ESSPRI was observed.

Possible future applications of B-cell targeting in Sjögren’s Syndrome, Bootsma hypothetised, might be a combination of first rituximab induction therapy followed by belimumab maintenance treatment. This hypothesis is based on translational research with histopathological and immunohistochemic studies if salivary gland tissues. Treatment should be focussed on prevention of tissue damage.

The research group of Bootsma herself presented long awaited data of T-cell targeting using abatacept in primary Sjögren’s Sydnrome. Petra Meiners gave an oral presentation (OP0112) and concluded that the open label phase II ASAP (Active Sjögren Abatacept Pilot) study delivered promising results both in terms of efficacy (ESSDAI and ESSPRI decrease) and safety/tolerance. A placebo-controlled study is scheduled to follow to confirm these data.
Anti-IL-6 targeting with tocilizumab will also be studied in France in the upcoming months.

My personal conclusion:

Whilst at this moment the bottom-line is that there is actually no news in terms of immediate available and applicable breakthrough treatment for the many patients that suffer Sjögren’s Sydnrome, the outlook is looking brighter the ever. Whereas early diagnosis is still a challenge, we now have good tools for measuring disease activity, disease damage, and disease burden. They facilitate stduy design and the search for effective treatment options, and combined with recent promising trial results summed up above as well as upcoming trials in the near future, all investigating efficacy of biological agents in Sjögren’sSyndrome, make future EULAR or ACR meetings definitely events to look out for for both rheumatologists and patients. There seems defintely “more to follow…”! 

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