Table 2

Summary-of-findings table generated for prospective studies in primary-2002 patients with Sjögren syndrome

Author (year)PatientsDesign (duration)Intervention, dose (patients)Comparison (patients)Efficacy parameters (p<0.05)Safety profile
Significant associations (p<0.05)Non-significant associations (p>0.05)
Kedor et al (2016)2630Prospective (16 w)Oral cyclosporine A, approx 2 mg/kg/day (n=30)NoneTender joint count (0.001), swollen joint count (<0.001), DAS28 (<0.001), ESSDAI (<0.001), gammaglobulin (0.009), anti-La (0.048)Patient’s disease activity (p=0.249), pain (p=0.094), fatigue (p=0.350),SF-36 total (p=0.259), HAQ-DI (p=0.372), CRP mean (p=0.780), ESR mean (p=0.268), IgG mean (p=0.360), Schirmer’s test (p=0.820), Saxon’s test (p=0.925), anti-Ro (SSA) 60 kDa (p=0.786), anti-Ro (SSA) 52 kDa (p=0.400), RF (p=0.099)All had experienced at least one adverse event (AE): gastrointestinal (70%), muscle craps (67%), nervous system (53%), skin (53%); infections (30%) of mild or moderate severity occurred 13 times in 10 patients; drop-out 6/28 (21%)
Egrilmez et al (2011)2022Prospective (12 m)Plug (n=22)NoneSchirmer test (0.006), BUT (<0.001)Visual acuity levels (p=0.608), lissamine green staining scores (p=0.958)Pyogenic granuloma (n=1)
Aragona et al (2006)2115ProspectivePilocarpineNADry mouth (<0.001)VARS for systemic symptoms (NS): skin dryness, vagina dryness.Sweating in 6 (40%), chill in 3 (20%), nausea in 2 (13%), oversalivation in 2 (13%), gastritis in 1 (7%)
(2 m)5 mg/6 hours (progress increase of dose)Ocular burning, foreign body (<0.02)VARS for ocular symptoms (NS): itching, mucus secretion, photophobia, hyperaemia, tearing.
Ocular tests results (NS): corneal fluorescein stain, Schirmer’s I, test basal secretion test
Yamada et al (2007)3013ProspectiveCevimeline 30 mgNoNo information about overall efficacyGroups according to positive or negative findings of:
  • sialography: age (p=0.700),

  • labial minor salivary gland biopsy: age (p=0.623), pretreatment

WSS (p=0.806), post-WSS (p=0.073)
  • anti-Ro/SSA antibodies: age (p=0.446), pretreatment WSS (p=0.268), post-WSS (p=0.165), increment rate (p=0.683)

  • anti-La/SSB: age (p=0.561), pretreatment WSS (p=0.914), post-WSS (p=0.116), increment rate (p=0.018)

  • Disease duration (months): age (p=0.917), pretreatment WSS (p=0.934), post-WSS (p=0.950), increment rate (p=1.000)

No serious adverse effects
(4 w)One time daily (first 2 w)Higher increase of WWS in patients with:
Two times (next 2 w)Negative sialography (0.042), negative La (0.018) and negative bx (0.002)
Yavuz et al (2011)3132ProspectiveHCQ 6.5 mg/kg/day (>2 years)NoSymptom severity score (<0.001)OSDI (NS), Schirmer’s test (mm) NS, Schirmer’s test with anaesthesia
(mm) NS, average tear drop/day NS, NEI-VFQ-25 questionnaire (NS)
Not detailed
(12 w)Tear BUT (0.001) corneal fluorescein (0.01)
Oxford score (0.003)
Cankaya et al (2010)3230ProspectiveHCQ 400 mg/dayNoMean uSFR (<0.05)Dry mouth (p=0.292), burning oral mucosa (p=0.11), difficulty in mastication (p=0.969)Not detailed
(30 w)
van Woerkom et al (2007)2715ProspectiveLeflunomide 20 mg/24 hoursNoMFI (0.034)VAS general health (p=0.529), VAS dry eyes (p=0.361), VAS sandy feeling (p=0.343), VAS dry mouth (p=0.098), VAS sleep disturbance due to dryness (p=0.484), Zung depression score 37 (p=0.726), RAND (SF-36) mental component (p=0.790), ESR (p=0.200), CRP (p=0.453), Schirmer test (p=0.138), sialometry (p=0.632)All 15 patients suffered AEs; not classified as SAEs
(24 w)SF-36 physical component (0.026)Diarrhoea 7, GI discomfort 6, hair loss 7, weight loss >2 kg 5
Reduced serum IgA (0.023), IgG (0.006) and IgM (0.005)Headache 5, LE skin lesions 5, anaemia 5, leucop 4, dizziness 4
Reduced RF levels (0.045)TAS 3, rashes 4 (different patients of LE rashes)
Willeke et al (2007)2811ProspectiveMycophenolic acidNoVAS sicca (<0.02)Schirmer's test (millimetres per 5 min), whole saliva (grams per 5 min), VAS arthralgia, VAS fatigue, Health Assessment Questionnaire score, erythrocyte sedimentation rate (mm/hour), IgG (mg/dL), IgA (mg/dL), anti-SSA antibodies, anti-SSB antibodies. No changes in the 28-swollen/tender joint count or in the number of tender points were observed (data not shown). No significant changes concerning the Raynaud syndrome were observed.Three withdrawals (one pneumonia)
(24 w)Increased doseMean AT use (<0.02)Total AE: 7/11 (63%); not classified as SAEs
(360 mg to 1440 mg daily)Reduct gammaglobulins, C3 and C4 levels (<0.02)GI discomfort=5, herpes=1, common cold=2
Reduct IgM, RF (<0.05)
Increased leucocytes (<0.05)Dose reduction in 2
General health, role emotional SF-36 domains (<0.05)
Zandbelt et al (2004)29ProspectiveEtanercept 25 mg twice per weekNoCRP (<0.05)ESR (p=0.058), gammaglobulin (p>0.05), Schirmer-I tests (p>0.05), SL/SM salivary (p>0.05), flow measurements (p>0.05), BUT or rose bengal staining (NS, data not shown). Post-treatment LFS (p=0.101) and IgA% (p=0.621). Raynaud syndrome (NS).Infectious parotiditis (n=1)
12 w(n=15)General fatigue scale within the MFI (p=0.018)
VAS score for perceived disease activity (p=0.045)
Pijpe et al (2005)3315Prospective (12 w)Rituximab 375 mg/m2NoOnly in the subset ‘early’: rose bengal, BUT, MFI, SF-36 PF, V, HC (<0.05)Either group of patients: levels of IgG, IgA, IgM, and 2-microglobulin did not change.
Patients with MALT/primary SS: No changes in T-cell subsets
All patients (>0.05): whole saliva, stimulated submandibular/sublingual salivary secretion.Schirmer’s test.
Patients with MALT/primary SS: rose bengal, BUT, MFI, SF-36 PF, V, HC (>0.05)
Infusion-related (n=2), Herpes zoster (n=1), HACAs: 4/8 of early SS, 0/7 in MALT group, serum sickness (n=3), all HACA+
Devauchelle-Pensec et al (2007)3416Prospective (36 w)Rituximab 375 mg/m2NoGlobal VAS (0.03), pain VAS (0.006), fatigue VAS (0.006), dryness VAS (0.006), tender point count (0.027), tender joint count (0.017), IgA-RF (0.04)Ocular and oral dryness (p>0.05), swollen joint count (p=0.15), salivary flow rate, mL/min (p=0.86), Schirmer test (p=0.79), anti-SSA (p=0.25).
ESR (p=0.6), Latex test (p=0.1), IgA (p=0.7), IgG (p=0.2), IgM (p=0.2)
Infusion-related (n=2), lymphoma (n=1), delayed reactions (n=8), serum sickness (n=4)
St Clair et al (2013)3512Prospective (26 w)Rituximab 375 mg/m2NoGlobal VAS physician (0.012) and patient (0.009), VAS tongue dryness (0.007), level of thirst (0.005), oral discomfort (0.02), fatigue (0.042)Joint pain (p=0.077), unstimulated (p=0.287) or stimulated (p=0.718) whole salivary flow, RF (p=0.109) p≥0.05: Tear production, Schirmer’s test, ocular surface dryness (von Bijsterveld scoring system), SF-36 for physical and mental functioning between week 0 and week 26.Severe AE reaction to pneumococcal vaccine (n=1); non-severe (n=2), squamous cell carcinoma (+301 d)
Carubbi et al (2013)3641Case control (120 w)Rituximab 1 g/15 d (n=22)DMARD treatment (n=19)ESSDAI reduction RTX vs DMARD (<0.05)Unstimulated salivary flow and the Schirmer’s I test were not affected in the DMARD treatment group.No adverse events
Global VAS (<0.05), fatigue VAS (<0.01), dryness VAS (<0.01), physician VAS (<0.05), uSF (<0.01), Schirmer (<0.05)p>0.05: IgG, ANA, RF, anti-Ro/SSA and anti-La/SSB antibodiesNo withdrawals
Mariette et al (2015)5730Prospective (28 w)Belimumab 10 mg/kgNoDryness VAS (0.0021), ESSPRI (0.0174), ESSDAI (0.0015)Unstimulated whole salivary flow (p=0.27) or Schirmer’s test (p=0.51), even in SF-36 physical health and mental health component (p=0.71)
The focus score of the lymphoid labial salivary gland (LSG) infiltrate (p=0.57).
Mean baseline BAFF level (p=0.57)
Decrease of three points or more of ESSDAI (p=0.44).
Pneumococcal meningitis (n=1), breast cancer (n=1), scleroderma (n=1), pneumonia (n=1), headache (n=9), sinusitis (n=1), neutropenia (n=5), Rhinitis/pharyngitis (n=7), oral aphtosis (n=1), bronchitis (n=1), Herpes labialis (n=1), urinary tract infection (n=2), gastroenteritis/diarrhoea (n=2)
ESSDAI glandular (0.0078), biologic (0.0078), articular (0.0313)
De Vita et al (2015)2219Prospective extension (52 w)Belimumab 10 mg/kgNoPhysician VAS (0.04), RF (0.048), IgM (<0.01) Glandular domain (p=0.0078)
Articular domain (p=0.0313)
Biologic domain (p=0.0078)
VAS dryness score (p=1.0), VAS fatigue (p=0.14)
VAS pain (p=0.71), biologic improvement (p=1.0) at W28 and W52.
VAS score of disease systemic activity by the physician at W28 (p=0.65), p>0.05: SF-36 physical health, mental health component
uSFR (p=0.6), Schirmer’s I test (p=0.3)
Focus score of labial salivary gland biopsy (p=0.9)
Lymphadenopathy domain (p=0.0625)
Rhinopharingitis (n=2), headache at the end of the infusion (n=1), gastroenteritis (n=1), mild transient neutropenia (n=2), urinary tract infection (n=1), pneumonia (n=1), vaginal fungal infection (n=1), non-complicated cutaneous infection (n=1)
Steinfled et al (2006)16Prospective (18 w)Epratuzumab 360 mg/m2NoVAS fatigue (<0.05), patient assessment (<0.05), physician assessment (<0.05), tender joints (<0.05)p>0.05: CRP; ESR; Ig, pain, changes from baseline in T cellsSevere infusion related (n=1) (discontinued), sinusitis (n=1), transient ischaemic attack with secondary seizure (n=1), moderate grade-3 acute infusion reaction (n=1), discontinued at third infusion, dental abscess (n=1), osteoporotic fracture (n=1), mild infusion related (n=2), headache, paresthesia (n=3), fever, palpitation, bone pain, carpal tunnel syndrome, diarrhoea, and dyspepsia (ND)
Meiners et al (2014)2415Prospective (48 w)Abatacept 10 mg/kgNoESSDAI (<0.05), ESSPRI (<0.05), Patient’s GDA (<0.05), Physician’s GDA (<0.05), RF (klU/L) (<0.05), IgG (g/L) (<0.05)ESSDAI at W48 from baseline (p=0.137)
ESSPRI post-treatment (p=0.151)
Unstimulated whole saliva, parotid flow rate and lacrimal gland function, patient’s GDA, parotid saliva, stimulated (mL/min), Schirmer (mm/5 min): NS.
No SAEs occurred, and no patients withdrew from the study due to AEs.
Mild infusion reaction (n=1); mild acute AEs -dizziness, hypotension- (17 events in 6 patients)
18 self-reported infections (18 infections in 10 patients), the most common being upper respiratory tract infections. No infection required hospitalisation.
Adler et al (2013)2511Prospective (108 w)Abatacept 500–750 mgNoNumbers of lymphocytic foci decreased (0.041), numbers of local FoxP3, T cells decreased (0.037), peripheral blood, B cells increased (0.038), expansion of the naive B cell pool (0.034)Histology (NS): Lymphocytic foci/mm2, CD20 B cells, CD3 T cells, mm2, CD20 B cells, CD3 T cells, CD4 T cells, CD8 T cells.No serious adverse events, no infusion reactions
Total lymphocytes increase (0.044) and for CD4 cells (0.009)Serum (NS): IgG, g/LTransient increase in liver enzymes (concomitant rifampin) (n=1)
Gamma globulins decreased (0.005)Peripheral blood cells (NS): lymphocytes, CD3 T cells, CD4 T cells, CD8 T cells, memory B cells, switched memory B cells, non-switched memory B cellsDiverticulitis (n=1)
Saliva production increased (0.029)Lupus-like skin lesions (n=1)
  • AEs, serious adverse events; ANA, antinuclear antibody; AT, artificial tears; BAFF, B-Cell Activating Factor; BUT, tear breakup time; bx, biopsy; CRP, C-reactive protein; DAS, disease activity score; DMARD, Disease-modifying anti-rheumatic drug; ESR, erythrocyte sedimentation rate; ESSDAI, EULAR Sjögren's syndrome disease activity index; ESSPRI, EULAR Sjogren's Syndrome Patient Reported Index; GDA, global disease activity; GI, gastrointestinal; HACA, human antichimeric antibodies; HAQ-DI, Health assessment questionnaire disability index; HC, health change; HCQ, hydroxychloroquine; LE, lupus erythematosus; LFS, lymphocyte focus score; m, month; MALT, mucosa-associated lymphoid tissue–type lymphom; MFI, Multidimensional Fatigue Inventory; ND, not detailed; NEI-VFQ-25, National Eye Institute-Visual Function Questionnaire-25; NS, not significant; OSDI, Ocular Surface Disease Index; PF, physical functioning; RF, rheumatoid factor; RTX, rituximab; SAEs, serious adverse events; SF-36, Short Form-36 Health Survey; SL/SM salivary, sublingual/submandibular gland; TAS, taste; uSFR, unstimulated salivary flow rate; V, vitality; VARS, Visual analogue rating scales; VAS, visual analogue scale; w, week; WSS, Whole stimulated sialometry.