Summary-of-findings table generated for prospective studies in primary-2002 patients with Sjögren syndrome
| Author (year) | Patients | Design (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)26 | 30 | Prospective (16 w) | Oral cyclosporine A, approx 2 mg/kg/day (n=30) | None | Tender 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)20 | 22 | Prospective (12 m) | Plug (n=22) | None | Schirmer 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)21 | 15 | Prospective | Pilocarpine | NA | Dry 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)30 | 13 | Prospective | Cevimeline 30 mg | No | No information about overall efficacy | Groups according to positive or negative findings of:
WSS (p=0.806), post-WSS (p=0.073)
| 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)31 | 32 | Prospective | HCQ 6.5 mg/kg/day (>2 years) | No | Symptom 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)32 | 30 | Prospective | HCQ 400 mg/day | No | Mean 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)27 | 15 | Prospective | Leflunomide 20 mg/24 hours | No | MFI (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)28 | 11 | Prospective | Mycophenolic acid | No | VAS 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 dose | Mean 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)29 | Prospective | Etanercept 25 mg twice per week | No | CRP (<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)33 | 15 | Prospective (12 w) | Rituximab 375 mg/m2 | No | Only 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)34 | 16 | Prospective (36 w) | Rituximab 375 mg/m2 | No | Global 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)35 | 12 | Prospective (26 w) | Rituximab 375 mg/m2 | No | Global 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)36 | 41 | Case 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 antibodies | No withdrawals | |||||
| Mariette et al (2015)57 | 30 | Prospective (28 w) | Belimumab 10 mg/kg | No | Dryness 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)22 | 19 | Prospective extension (52 w) | Belimumab 10 mg/kg | No | Physician 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) | 16 | Prospective (18 w) | Epratuzumab 360 mg/m2 | No | VAS 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 cells | Severe 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)24 | 15 | Prospective (48 w) | Abatacept 10 mg/kg | No | ESSDAI (<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)25 | 11 | Prospective (108 w) | Abatacept 500–750 mg | No | Numbers 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/L | Transient 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 cells | Diverticulitis (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.