Index

A

Abatacept (CTLA-4 Ig), 465, 477 Abnormal light sensitivity, see Photophobia Acetylcholine (ACh)

acinar cells, 153, 154f

muscarinic receptor, 159, 205, 473 neurotransmitter, 26, 153, 154f, 484 PGPN releasing, 155f, 156, 205, 251 physiological responses, 117

saliva secretion, 118f secretagogue, 154, 198 secretion, 165

Acinar cells, 77f, 118f, 155f, 248f acetylcholine, 153, 154f

autonomic nervous system stimulation, 154

cell innervation and humoral immunity, 251–252 exocrine gland functions (resting/stimulation phase)

parasympathetic nervous system, 154 sympathetic nervous system, 153

myoepithelial cells function (resting/filling phase), 154

Acute cerebellar ataxia, 386 Acute transverse myelitis, 390

Aerobic exercise and fatigue, 13, 364 Albumin-cytological dissociation, 387 Alefacept, 466

Alkylator lung, 391

Alzheimer’s disease, 4, 385, 389, 485

American College of Rheumatology (ACR), 6, 16, 18, 37, 40t, 42, 62, 65, 302t, 361, 367, 457, 474

American–European Consensus criteria, 12, 39t, 62–65, 64t, 253, 270–271, 278, 360, 406, 425, 437, 456

Amyloid neuropathy, 383

Anesthesia and surgery, 5t, 17t, 29, 38t, 64t, 75, 76f, 184–185, 208, 309t, 331, 348t, 381

Anhidrosis, 307, 379–380, 382

Anterior chamber-associated immune deviation (ACAID), 206

Anti-α(alpha)-fodrin, 112t, 114, 119, 250, 431 Anti-cardiolipin (ACL) syndrome, 378, 387

Anti-CD20, 44, 257, 347, 364, 413, 475, 477 Anti-CD22, 364, 477

Antidepressants, 23, 179, 182, 186, 339t, 340 Antihistamines, 179, 182, 186, 275, 277, 280, 305, 322 Anti-idiotypic antibodies, 141f, 142f

with antigen-binding sites, 140 anti-La/SSB antibodies, 141 molecular recognition theory, 140–141 NLS, 141

PR3 or cPR3, 141

Anti-M3 receptor (M3R), 112t, 117–118, 251–252, 385, 431

Anti-mycotics, 221

Anti-nuclear antibody (ANA), 18–19, 21, 21f, 24–25, 36–37, 39t, 40t, 43, 95, 98, 113, 141–142, 289, 294, 297, 301, 301t, 303f, 305–306, 327, 340, 374, 384, 388–389, 426t, 427, 434

Antioxidants, 23 Apoptosis

CTLA-4, 101–102 epithelial cells, 247 α-fodrin antibody, 119

initiation/recognition/effector phase, 121–125 M3R autoantibodies, 117

Ro60/Ro52 autoantigen, 138–139 in salivary glands, 253–254, 472 SS-A/Ro and SS-B/La, 115–116 T cells, 206, 211

Aquaporins (AQPs), 118, 248f, 252–253, 293, 296, 465, 473, 477, 487

Aqueous tear deficiency, 199 Areflexia, 381

Arthralgia

and arthritis, treatment of, 323–324 anti-malarials, 323 cyclosporine, 324

DMARDs, 323 hydroxychloroquine, 324 leflunomide, 324 methotrexate (MTX), 324 Plaquenil, 324

sulfasalazine and azathioprine, 324

Arthralgia (cont.)

or arthropathy, joint/muscle manifestations, 291–292 chronic arthritis, 291

Lupus or Jaccoud’s arthropathy, 291 monoarticular or pauciarticular arthropathy, 291 osteoarthritis and erosive osteoarthritis, 291 rheumatoid factor, 291

Arthritis chronic, 291

JRA and JIA, 101, 306 non-erosive, 299, 302t, 340 osteoarthritis, 289, 317t, 358

rheumatoid, see Rheumatoid arthritis (RA) See also Arthralgia

Artificial saliva, 16, 29, 309t

Artificial tears, 47t, 188t–191t, 192t–193t, 196t, 197t, 309t, 419f

guidelines, 194–195 teardrops, 187, 199, 419 therapies, 195–197

Lacriserts, 196

Lotemax, 195

mild topical steroids, 195 pilocarpine, 197 secretagogues, 197

from umbilical cord blood, 196 use of autologous serum tears, 196

types, 195

Aseptic meningoencephalitis, 386 Athetosis, 380–381

Australia, 423–424 anti-Ro-La responses, 424 BAFF/BLyS, 424

clinical features, 423 complications, 423

secondary Sjögren’s syndrome, 425 treatment, 424

hydroxychloroquine, 424 methotrexate, 424 sodium bicarbonate, 424 topical lubricants, 424 use of rituximab, 424

Autoantibodies and autoantigens anti-α-fodrin antibody, 119

antibodies to nuclear protein NA14, 119–121 anti-muscarinic type 3 receptor (M3R)

autoantibodies, 116–118 anti-SS-A/Ro and anti-SS-B/La antibodies,

113–116

major factors of autoantibody production effector phase, 125

establishment phase, 123–124 initiation phase, 121–122 recognition phase, 122–123

prevalence of autoantibodies, 112t secretion, 472

genetic and environmental factors, 472f innate and adaptive immunity, 472f

Autoantigen, see Autoantibodies and autoantigens

Autoimmune disorder, 4, 20, 23, 37, 43, 100, 143–144, 227, 290, 318, 388, 415, 424, 455, 457–458, 462, 490

Autoimmunity, 95, 101, 103, 104f, 115, 123–124, 134, 141–143, 193, 209, 249, 254, 256–258, 274, 277, 438, 460–462, 470–472, 474, 484

Autologous serum eye drops, 416

comparison of tears and autologous serum, 417t future studies, 419–420

preparation of, 417, 418f research, 417

for Sjogren’s and non-Sjogren’s Syndrome, 418–419 Autonomic nervous system (ANS), 118, 153–154, 156,

382, 461, 483–484 Autonomic neuropathies, 308t, 320t

cardiovascular tests, 24, 296 diagnosis and treatment, 383 etiopathogenesis, 484

finger skin blood flow test, 24 gastrointestinal manifestations, 297 lSBP/lDBP ratio, 24

orthostatic test, 24 sympathetic dysfunction, 24 vagal dysfunction, 24

Azathioprine, 308t, 319t–321t, 324–326, 329, 333, 339t, 340–341, 386, 390, 427, 431, 434

B

Bacterial meningitis, 384 Barrett’s metaplasia (BM), 278

Basal tears, 28, 181–182, 185, 198, 416, 417t Bayesian analysis, 6, 19

B-cell activating factor (BAFF), 99t anti-TNF, 474

autoimmune diseases, 255–256 BLyS, 470, 470f

IFN–BAFF–B-lymphocyte axis, 474–477 inhibition, 464

multiple cellular origins, 470–471 overexpression, 471

receptors and classes, 168 secretion, 471–472

B-cell depletion anti-CD22, 463, 477

rituximab, 462–463, 475–477 B-cell epitopes, 133–145

clinical significance/specific HLA associations, 140 definition/identification, 134

of intracellular autoantigens, classification, 134–140, 134f

cryptic epitopes (cryptotopes), 135 modified epitopes (neoepitopes), 135 primary structure epitopes, 134 quaternary structure epitopes, 135 secondary structure epitopes, 134–135 tertiary structure epitopes, 135

for investigation of autoimmune response, 140–144 complementary epitopes and anti-idiotypic

antibodies, 140–141

early epitope recognition/spreading, 142–143 post-translational modifications (PTMs), 143–144

La/SSB, 135–137

Multifunctional Chaperone Calreticulin, 139–140 functions, 139–140

Ro epitopes, 140

Ro52 autoantigen, 139, 139f epitopes of, 139 functions, 139

Ro60 autoantigen, 137–139, 137f apotopes and apoptosis, 138–139 epitopes of, 137–138, 138f structure and function, 137, 137f

Ro/La RNP particles, 135 B cells

anti-Ro and anti-La antibodies, 250 in BAFF, 471, 475

B lymphocytes, 166

CD27+ memory B cells, 250 cells in TACI–/– mice, 470 memory, 462

peripheral, 462–463

in salivary glands, 244, 256, 258 V(L) gene analysis, 250

Biofilm/plaque formation, 237–238 Biological therapies, 459–466

BAFF inhibition, 464

belimumab (Lymphostat B), 464 B-cell depletion, 462–463

rheumatoid factor and anti-SSA/SSB antibodies, 463

rituximab, 462–463 gene therapy, 465

adeno-associated virus (AAV), 465 IL-10 gene delivery, 465

rAAV2, 465

interferon inhibition, 464–465 low doses of IFN-α, 464 viral infection, 464

monoclonal antibody modulation of B-cell function, 463–464

epratuzumab, 463–464 scientific rationale, 460–461 lymphocytes, 460–461

T and B cells, 461 TNF-α(alpha) inhibition, 461–462

etanercept, 462 infliximab, 461

Biologics, 455–457, 461 Biomarkers, 112

analyses in saliva, 227–228 BAFF, CCL11, and IFN-γ, 250 of LFU dysfunction, 214 miRNAs, 484

in serum, 227, 250, 462 Biopsies

brain, 385 conjunctival, 27

histopathology/glandular, 73–79

benign lymphoepithelial lesion in salivary glands, 74–75

degree of inflammation by focus score, 77f ectopic germinal center formation, 79 focal infiltration, 78–79

major salivary gland biopsy in SS, 75, 77f minor salivary gland biopsy in SS, 74f, 75–78

labial minor salivary gland, 409, 426, 431

lip, 4, 26, 62, 84, 244, 305, 393, 410, 410t, 427 liver, 297, 341

lung, 295

muscular, 25, 386, 390 parotid, 75, 271, 348–349, 348f renal, 325, 333, 341

skin, 288, 290, 377, 386, 394 sural nerve, 29, 377, 393

Bite guard, 410–413

maintenance of saliva volume, 412 night guard, 411, 411f

rhythmic masticatory muscle activity, 412 visual analog scale (VAS), 412, 412t

Blepharitis, 22, 45t, 46–47, 47t, 48t–49t, 67, 67t, 183, 186–187, 192, 196t, 212, 305t

Boston Lens, 193

Botox R injection (keratoconjunctivitis sicca), 28 British Isles Lupus Activity Group (BILAG) scoring

system, 66, 445t, 446t, 447 Burning mouth, 18f, 23, 54t, 272, 321t, 374

C

Candida albicans

anti-fungal medications, 238 infections, 238

topical application, 238

Caries preventive measures, 233–239 control of plaque/biofilm formation, 237 dietary advice, 237

teeth and saliva, 233–237 fluorides, 231–232, 234f salivary substitutes, 236–237 stimulation, 234–236

time factor, 238

See also Dental caries Cell-mediated immunity

epidermal nerve fiber density, 377 lymphocytic/necrotizing vasculitis, 377 motor neuropathies, 377

sural nerve biopsies, 377 vasculopathy, 377–378 vicious cycle, 378

Central nervous system (CNS) manifestations, 383–387 aseptic meningoencephalitis, 386

cognitive impairment, 385 inflammatory disease, 383–385

diplopia and ataxia, 384

gray matter dysfunction (spasticity and hyperreflexia), 383–384

intracranial vasculitis or vasculopathy, 385 multiple sclerosis, 384–385

Central nervous system (CNS) (cont.) myelitis, 383

neuromyelitis optica (NMO, Devic’s syndrome), 384

optic neuritis, 384 investigations of

cerebral angiography, 388 MRI, 387–388

nuclear brain imaging studies, 388 serology, 387

spinal fluid, 387 movement disorders, 385–386

neurological disorders, 386–387 objective abnormalities, 374 treatment, 389–391

combination therapy, 390 myalgias, 390

prednisone and cyclophosphamide, 390 rituximab/IV-Ig/plasma exchange, 390 steroids, 390

Central pain sensitization, 388 Cerebral venous thrombosis, 386 Cevimeline

dry mouth, 234, 406 Evoxac R , 235

labial minor salivary gland biopsy, 409 saliva prodution, 154, 405–406, 410 sialography, 409–410

tear flow, 198

whole stimulated sialometry (WSS), 407–408, 408f, 410f

xerostomia, 231t

Chemokines, 121, 124, 165–168, 209, 211, 213, 229, 244, 245f, 247, 250, 374, 378, 394, 424, 460, 465–466, 471–472, 477, 487

China, SS in, 429–432 azathioprine, 434 cardiac disease, 434

clinical features and treatment, 430 complications, 431, 431t

Dental caries, 435

Disease of Antiquity in Ancient China, 429–431 gastrointestinal disease—protein-losing enteropathy,

434 HR-QOL, 434–435

multiple specialties, 430, 430t

novel autoantibodies in diagnosis, 431 peripheral neuropathy, 434

pSS, 433–434

pulmonary complications, 434 rituximab and TCM, 431–432 SLE, 431

Zao Bi (dry eyes/mouth with glandular swelling), 429 Chlorhexidine, 52t, 234, 237, 239

Cholinergic anti-inflammatory pathway, 154, 484 Chronic cough, 276, 320, 324–325

Chronic foreign body sensation, see Grittiness

Chronic inflammation, 78, 121, 161–162, 166, 168, 181, 205, 212, 244–245, 254, 258, 345

Chronic inflammatory demyelinating polyneuropathy (CIDP), 377–378, 382, 449t–450t

Classification criteria, 59–70

Epidemiology Committee of the Commission of the European Communities, 62–65

EULAR Project, 69–70 Italian study, 67–69

outcome measures in SS, 65–66

for primary SS, comparison, 60–62, 71t for SLE, 42

SSclinical activity index (SCAI), 66–67 SS damage index (SSDI), 66–67

for SS, revised, 5t, 19t, 38t, 39 Clinical disease spectrum, 437 Clinical practice guidelines, 456, 458

Facilitator for Both Initiatives, 458 Ocular Working Group, 458

Oral Working Group, 458 Rheumatology Working Group, 458 SSF Clinical Trials Consortium, 458

Clinical trials in pSS, 357–368 dryness (sicca) symptoms

data addressing, 366–367 measurement of, 364–366

fatigue, 358

measurement and extraglandular symptoms, 361–363, 360f

potential approaches and extraglandular symptoms, 364

potential causes, 358–361

health status/health-related QOL, 363 Clonazepam, 23, 54t, 386

Cognitive impairment, 385 characterization, 385 clinical presentation, 385 Kawashima, 385 reversible dementia, 385

Computers, patient access to, 15–16, 26, 35–36, 181 Computer tomography (CT), 84–85, 271, 295, 306, 341,

348–349, 386, 434

Congenital heart block (CHB), 115–116, 139, 142f, 296, 299, 308t, 321t

Conjunctivitis medicamentosa, 186

Connective tissue diseases (CTDs), 59–60, 62, 294 Contact lenses, 181, 186, 193, 197–198, 393 Copenhagen criteria, 60–62, 61t, 152, 430 Corneal sensitivity, 181, 186, 189

Corneal staining, 192, 367 Corneal thinning, 186 Corneal topography, 185

Corneal ulcers, 45t, 67t, 186, 305t Cosmetic procedures

Blepharoplasty (basal tearing), 29

Botox R injection (keratoconjunctivitis sicca), 29 complications, 198

LASIK surgery (pre-existing SS), 28 Criteria fibromyalgia, 41t–42t, 43 Criteria Sjogren’s syndrome, 37, 38t–39t

Criteria systemic lupus erythematosus, 39t–40t, 42

Criteria systemic sclerosis (sceleroderma), 40t–41t, 42 Crohn’s disease, 94, 96, 327, 466

Cryoglobulinemia, 12, 22, 25, 66t, 288, 290, 297–298, 307t–308t, 319t–320t, 326, 338, 341, 346, 350f, 378, 424, 449t–450t, 460, 462, 475

Cutaneous vasculitis, 25, 288, 307, 448t Cyclosporine-A, 187, 192, 193, 195

Cysteine-rich secretory protein 3 (crisp3) levels, 27, 293

Cytokines, 167–168, 358–359

BlyS/BAFF, 168, 359 C57BL/6 J mice, 168 IFN-α/β system, 167 IL-17/IL-18, 168 PROFAD measure, 359

pSS/RA/SLE, distinction between, 359 SCAI, 359

secretory function, 167–168 Th1/Th2 cytokines, 167

Cytotoxic T lymphocyte-associated protein-4 (CTLA-4), 97, 101–102, 247, 253, 465–466

D

Damage index, 7, 18, 44, 45t, 65–68, 66t, 67t, 305t, 321 Danazol, 342

Degeneration, 76, 77f, 198, 205, 377–378, 381, 487 Deglutition problems, 24, 272 Dehydroepiandrosterone (DHEA), 28, 159–165, 160f,

162f, 163f, 198, 292–293, 308t, 320t, 330, 359, 364

Delphi model, 44, 62, 180, 456

Demyelinating polyneuropathy, 378, 382, 449t–450t Dental caries

in China, 435 development of, 230 due to xerostomia, 272f

plaque and biofilm formation, 236 prevention/treatment, 47–49, 49t–51t

Dentocult R SM or Dentocult R , 237–238 Dermatosis, 290

Diabetic and non-diabetic radiculoplexus neuropathies, 382

Diagnostic dyes, 183 Diagnostic fluid

biomarker analyses in saliva, 227–228 biofluids, 228

protein in serum, 227 serum–saliva recovery rate, 227

dripping method, 227 exploration of saliva, 228–230

biomarkers, 229–230

comprehensive bead and antibodybased multiplex assays, 229

2D gel electrophoresis-based mass spectrometry,

229

immunofluorescence/in situ hybridization, 228 mass spectrometry-based studies, 229

oral cavity, 228

Ro/SSA and La/SSB, 228

salivary flow rates, 228 surface-enhanced laser desorption, 229

gland specific or whole saliva, 226 Diffuse myalgia (fibromyalgia), 388

Diffuse parenchymal lung disease (DPLD), 294 Diffusion tensor imaging (DTI), 387

Disease activity index, 7, 44, 45t–46t, 46, 68–69, 68t, 444, 445t–446t, 447, 448t

See also EULAR Disease Activity Scores Disease damage index, 7, 18, 45, 45t, 67t, 68, 305t Disease-modifying anti-rheumatic drugs (DMARDs),

323, 339–340, 339t, 349 Dry eye management, 22, 179–200 artificial tears, 190t–191t, 196t

guidelines, 194–195 therapies, 198–199 types, 193

diagnostic screening examination, 183–185 corneal topography, 185

diagnostic dyes, 183 fluorescein, 183 Lissamine Green, 184

measurements of tear film osmolarity, 185 Rose Bengal, 183–184

Schirmer’s test, 184–185 tear film breakup time, 184

factors affecting, 180

four levels of severity differentiation, 186–193 Level 1 (mild-to-moderate symptoms), 186–187,

188t–189t

Level 2 (moderate-to-severe symptoms), 187 Level 3 (artificial tears/cyclosporine-A/restasis),

187–191, 190t–191t

Level 4 (severe symptoms), 192–193 incidence, 180

with interferon gamma signature, 27 moisture preservation and oral medications

moisture chambers, humidifiers, and contact lenses, 197

punctal plugs, 197

ophthalmologic cosmetic procedures, complications LASIK and refractive surgery, 199

LASIK vision-corrective surgery, 199 PRK, 199

oral medications and supplements

dietary fatty acids (flaxseed oil) and dry eyes, 198

oral medications, 198–199 patient, rules for, 47t

quality of life and patients complains, 182 abnormal light sensitivity (photophobia), 182 chronic foreign body sensation (grittiness), 182 excessive tearing (epiphora), 182

tenacious mucus in eyes, 182 rules for dry eye patient, 196t

side effects and monitoring, 185–186 blepharitis, 186

conjunctivitis medicamentosa, 186 contact lens use, 186

Dry eye management (cont.) corneal thinning, 186 corneal ulcers, 186 reduced tear flow, 186

symptomatic presentation, 180–181 tear selection, home points for, 199

Dry mouth in Japan, 405–413 bite guard, 410–413 cevimeline, 406–409

labial minor salivary gland biopsy, 409 sialography, 409–410

diagnosis, 406, 407f

immunological treatment for pSS, 413 products, 407t–408t

Revised Japanese criteria, 406, 407t Dryness, oral

assessment of, 223–226 hyposalivation, 224–226 xerostomia, 223–224

caries preventive measures, 233–238 control of plaque/biofilm formation, 237 dietary advice, 237

teeth and saliva, 233–237 time factor, 238

management of xerostomia, 230–233 Dryness (sicca) symptoms

clinical studies

interferon-α lozenges, 367 pilocarpine, 366 rituximab, 367

topical cyclosporine emulsion, 367 measurement of, 364–366

ocular surface disease index (OSDI), 366 Sicca Symptoms Inventory (SSI), 366, 366f

Dryness, vaginal, 329–330

estrogen replacement therapy, 330 lubricants, 329

vaginal atrophy, 330 yeast infection, 330

Dry skin manifestations

annular erythema—of Sjögren’s syndrome (AE–SS), 290

cryoglobulinemia, 288–289 cutaneous vasculitis, 288 dry skin, 286

Hypergammaglobulemic purpura, 288 non-vasculitic cutaneous manifestations, 290 Raynaud’s phenomenon, 290

urticarial vasculitis, 288, 290 treatment of, 321–323

broad-spectrum sunscreen, 322 moisturizer, 322

Neutrogena Sensitive Skin Sun Block SPF-30 R , 322

oral anti-histamines, 322 over-the-counter lotions, 322

routine skin checks for skin cancers, 322–323 skin cleansers, 322

topical corticosteroids, 322 Duraphat R , 50t, 233–234, 238 Dynamic touch allodynia, 391 Dysarthria, 381, 390 Dysautonomia, 484

Dysesthesia, 380–383

Dysfunctional tear disorder, 181, 184–185 Dyspareunia, 299, 307, 393

Dysphagia, 270t, 273f, 277–279, 277t, 297, 323, 328, 333 Dysphonia, 67, 275, 277

E

Eccoeye shields, 197 Efalizumab (Raptiva), 466

Electromyography (EMG) studies, 374, 379–380, 388, 393, 449t–450t

ELISA detection methods, 19, 43–44, 115, 117, 120f, 143, 252, 328, 389

Endothelial cells, 157t, 210f CXCL13, 166, 472 leukocyte interactions, 167

lymphocyte migration, 244, 245f neovascularization, 244

saliva secretion, 245

Endothelial-leukocyte adhesion molecule (ELAM)-1, 247 Endura, 48t, 187, 188t, 189, 190t

Epidemiology Committee of the Commission of the

European Communities, 62–65 American–European Consensus Group criteria, 63–65 European Classification Criteria, 62–63

ROC curve, 63 six-item criteria, 62–63

Epidermal growth factor (EGF), 164, 185, 208, 210, 213, 416–417, 417t

Epimyoepithelial islands, 74, 152 Epiphora, 182

Epistaxis, 270t, 275 Epithelial cells

APCs, 245, 247 apoptosis, 247

autoimmune epithelitis, 245 conjunctival, 115, 207 cytokines and chemokines, 247 MHC, 247

ocular surface, 209, 211

salivary gland, 105, 115, 123, 246–247, 473 SGEC lines, 246–247

TLRs, 247 Epratuzumab, 463–464

Epstein–Barr virus nuclear antigen (EBNA-1), 103, 104f, 116, 123, 142

Erythematous candidiasis, 23, 51, 272, 272t Erythrocyte sedimentation rate (ESR), 277, 300, 306,

324, 333, 340, 359, 376, 461–462, 464 E-selectin, 167, 245

Esophageal dysmotility, 41t, 42, 277–279, 277t, 297, 340 Esophageal manifestations, 277–279

autonomic neuropathy, 278 dysphagia, 277, 277t

esophageal web, 278 motility disorders, 278 treatment, 279–280 UES and LES, 277

Establishment phase, 123–124 aberrant cytokines production, 123

chronic focal periductal lymphocytic sialadenitis, 124

intermolecular–intrastructural help, 124 T-/B-lymphocyte hyperactivation, 123

Estrogen replacement therapy, 209, 330 Etanercept, 27, 279, 329, 461–462, 474 EULAR Disease Activity Scores, 443–453

disease activity index, 445t–446t evaluation of pSS patients’ symptoms

comparisons of scores, 451–453, 452t ESSPRI, 449, 451t

PROFAD, 449 SSI, 449

evaluation of systemic features of pSS comparisons of scores, 449 ESSDAI, 447, 448t–449t

SCAI, 447

SSDAI, 444

EULAR SS Disease Activity Index (ESSDAI), 69–70, 444, 445t–446t, 447, 448t–449t

EULAR SS Patients Reported Index (ESSPRI), 69–70, 444, 451, 452t, 453, 453t

Europe

criteria, 4, 16, 17t–18t, 39, 62–65, 76, 78, 224 ultrasound, 20

Excessive tearing, see Epiphora Extraglandular manifestations, 285–309, 304f

cardiac—heart disease manifestations, 295–296 accelerated atherosclerosis, 296

autonomic manifestations, 295 congenital heart block, 296 pericarditis, 295

cutaneous/dermatologic manifestations, 289–290 annular erythema—of Sjögren’s syndrome

(AE–SS), 290 cryoglobulinemia, 289–290 cutaneous vasculitis, 288 dry skin, 286

Hypergammaglobulemic purpura, 288 non-vasculitic cutaneous manifestations, 290 Raynaud’s phenomenon, 290

urticarial vasculitis, 288, 290 differential diagnosis of SS

medications and other metabolic disorders, 305–306

and scleroderma, 304

and SLE, 300–302, 301t–302t, 303f endocrinopathic/pancreatic manifestations, 292–294

adrenal insufficiency, 292–293 hypothyroidism, 292 pancreas, 293

gastrointestinal manifestations, 297 autonomic neuropathies, 297

dysphagia, 297

nausea, epigastric pain, and dyspepsia, 297 hematologic manifestations, 298

autoimmune neutropenia/thrombocytopenia, 298 chronic agranulocytosis, 299

Coombs’ positivity (hemolytic anemia), 298 leukopenia, 299

pure red blood cell aplasia, 299 hepatic and pancreatic manifestations, 297

autoimmune hepatitis, 297 autoimmune pancreatitis, 298

celiac disease (gluten-sensitive enteropathy), 298

idiopathic portal hypertension, 297 primary biliary cirrhosis (PBC), 297

joint/muscle manifestations (arthralgia/arthropathy), 291–292

chronic arthritis, 291 HLA-DR4, 291

Lupus or Jaccoud’s arthropathy, 291 monoarticular arthritis, 292

monoarticular or pauciarticular arthropathy, 291 osteoarthritis and erosive osteoarthritis, 291 rheumatoid factor, 291

late-breaking updates, 307–309 atopic dermatitis, 307 hypokalemic paralysis, 307 livedo reticularis, 307 nasal congestion, 308

non-specific interstitial pneumonitis (NSIP), 307–306

obstetrical/gynecological manifestations, 299 abnormal PAP smears, 299

congenital heart block, 299 vaginal dryness, 299

in pediatric population, 306 Henoch–Schönlein purpura (HSP), 306 juvenile inflammatory arthritis (JIA), 306 juvenile rheumatoid arthritis (JRA), 306 Kawasaki disease, 306

parotid gland swelling or lymphadenopathy, 306

precautions for SS patient undergoing general anesthesia, 309t

of pSS, 307t–308t

pulmonary manifestations, 294–295 interstitial lung disease (ILD), 294–295

renal/urological manifestations, 298 interstitial cystitis (IC), 298 interstitial nephritis (IN), 298

vasculitis, 300

classification and diagnosis, 300 CNS arteritis, 300

features, 300

Extraglandular manifestations, therapy of, 317–333 arthralgia/arthritis, 323–324

cutaneous manifestations Raynaud’s Phenomena, 323 treatment of dry skin, 321–323

Extraglandular manifestations (cont.) gastrointestinal manifestations

mesenteric vasculitis, 326–327 primary biliary cirrhosis, 327–329

obstetrical/gynecological manifestations vaginal dryness, 329–330

precautions at time of surgery, 330 pulmonary manifestations

chronic cough, 324–325

Interstitial Pneumonitis (NSIP), 325 renal manifestations

interstitial nephritis, 325–326 systemic features of pSS, 319t–321t urologic, 329

PBS/IC, 329 PPS, 329

therapies of interstitial cystitis, 329 vaccinations in SS patient, 331

herpes zoster vaccine, 331

live attenuated flu vaccine (LAV), 332 pneumococcal vaccine, 332

Extraglandular manifestations, treatment of, 337–342

management of fatigue, 340

gastrointestinal manifestations, 340–341 hematologic involvement, 342

kidney involvement, 341 liver involvement, 341 lung involvement, 341 musculoskeletal, 340

neurologic involvement, 342 Raynaud’s phenomenon, 340

in pSS, 339–340, 339t

extraepithelial manifestations, 338 periepithelial organ involvement, 338

F

Fanconi’s syndrome, 325, 341 Fatigue

aerobic exercise and, 13, 364 biological causes

cytokines, 358–359 neuroendocrine, 359–360 sleep, 360

brain-fog, 358

clinical trials in pSS, 358

measurement and extraglandular symptoms, 361–363, 362f

potential approaches and extraglandular symptoms, 364

potential causes, 358–361 disease-related fatigue, 358 extraglandular manifestations, 339

measurement and extraglandular symptoms, 361–363, 362f

medical conditions, 358

mental, 69–70, 360–362, 451, 452t, 453 muscle weakness, 358

physical, 362 psychosocial causes

depression, 360–361 fibromyalgia (FMA), 361

somatic, 362

treatment and extraglandular symptoms, 364 aerobic exercise, 364 dehydroepiandrosterone (DHEA), 364 infliximab, 364

rituximab and epratuzumab, 364 visual analog scale (VAS), 364, 365f

Fatigue Assessment Instrument (FAI), 361 Fatigue Severity Scale (FSS), 361 FDG-PET, 388

Fibromyalgia (FMA), 307t, 321t criteria, 41t–42t, 43

diffuse myalgia, 388 neurological manifestations, 388 in pSS, 361

symptoms, 4

Fibromyalgia syndrome (FMS)

Fibrosis, 40t–41t, 42, 45t, 66t, 67t, 76, 77f, 78, 83–84, 121, 244, 277, 297, 302t, 305t, 329, 387, 460, 483

Filamentary keratitis, 192

Fine-needle aspiration (FNA), 348, 350f Fluorides, 231t, 234f

retention of fluoride, 234 toothpastes, 233

topical fluoridation, 233 Fluor Protector R , 233–234, 238 Focal sialadenitis, 62

Focus score, 5t, 7, 17t, 38t, 61–62, 64t, 76, 77f, 78–79, 167, 301t, 407t

α-Fodrin antibody, 112t apoptosis, 119

membrane ion channels and pumps, 119 mouse models, 119

non-erythroid α-spectrin (calspectin or α-spectrin1), 119

Food and Drug Administration (FDA), 37, 46, 49t, 189, 198, 235, 293, 328, 456–457

Freund’s adjuvant, 255

Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale, 358

Fundoplication surgery, 279–280

G

Gastroenterology, 3, 285–309, 430t Gastro-esophageal reflux disease (GERD), 323 Gene(s)

CTLA-4, 101–102

cytokine expression patterns, 100 discovery, 95–97

FAS and FAS ligand, 102 genetic studies, 98–99

GSTM1, 102

innate immune disease mechanisms, 99 IRF5, 99–100

lymphocyte signaling molecules, 101 MBL, 100

MHC region, 100–101 polymorphisms, 101

PTPN22, 101 TGF- β(beta)1, 100

Gene therapy, 486f

adeno-associated virus (AAV), 465 AQP5 and AQP1, 487

IL-10 gene delivery, 465, 486 miRNA profiling, 485 pro-inflammatory molecules, 487 in pSS, 477

rAAV2, 465, 486

short hairpin RNAs (shRNAs), 487 vasoactive intestinal peptide (VIP), 486

Genetics, 21, 26–27, 94–95, 98, 101, 105 Genome-wide association (GWA) study approaches, 94,

96–97, 97f, 105 Genomics and viruses, 93–105, 97f

gene discovery, 95–97 genes in SS, 98–102 genetic component, 94–95

putative non-HLA candidate genes, 99t SLE and autoimmune diseases, 97–98 viral influences, 102–104

Germinal centers (GCs), 77f ectopic, 79, 123–124, 166, 251

like structure formation, 166, 250–251, 477 Glutathione-S-transferase MI (GSTM1), 102 Google Scholar, 4, 16

Grand mal seizures, 387

Gray matter dysfunction (spasticity and hyperreflexia), 383

Greek criteria, 60–61, 61t Greenspan’s criteria, 409 Grittiness, 182

H

Hashimoto’s thyroiditis, 97, 251

Helicobacter pylori infections, 79, 251, 294, 346 Henoch–Schönlein purpura (HSP), 300, 306, 327 Henrik Sjögren, recollection of, see Sweden Heparin plus aspirin, 333

Hepatitis C virus (HCV), 5t, 6, 63, 103, 121, 253, 289, 297

Herbs

Chinese, 28, 297–298

for life-threatening manifestations, 430 pilocarpine/quinine/salicylates, 429 TCPs, 429

Tea of Increased Tears, 429 Herpes zoster vaccine, 331–332 Herpetic keratitis, 286

Hormone replacement therapy, 209

Hospital Anxiety And Depression Scale (HADS), 360

Huang Di Nei Jing, 429

Human anti-chimeric antibodies (HACAs), 462

Human T-cell leukemia virus-1, 253 Hyaluronate eye drops, 419 Hyaluronic acid, 194t, 438

Hydroxychloroquine (HCQ), 24, 307t, 318, 319t, 321t, 323–324, 339t, 340, 364, 390, 424, 427, 438, 474

Hyperevaporation, 406

Hypertrophic cranial pachymeningitis, 386 Hypocomplementemia, 42, 339, 341, 382, 387, 450t Hypopituitarism, 387

Hyposalivation, 52t–53t, 230f, 277t nocturnal, 411

in NOD mice, 251–252 risk of tooth wear, 238 salivary dysfunction, 272 sialometry, 224–226

unstimulated/stimulated whole saliva measurement collection of saliva, 225

cut-off value, 226 flow rates, 226 tools, 225

xerostomia, 406

Hypothalamic–pituitary axis (HPA), 161–162, 359, 364

Hypothyroidism, 24, 279, 292, 327, 340, 358, 392, 431

I

Idiopathic neuropathy, 374, 388 Idiotypic network theory, 140

IgM paraproteinemic neuropathy, 381 Imaging technology

computer tomography (CT), 84–85, 271, 295, 306, 341, 348–349, 386, 434

diffusion tensor imaging (DTI), 387 laser Doppler imaging, 379

magnetic resonance imaging (MRI), 20, 83–87, 86f, 87t, 244, 271, 291, 300, 346f, 349, 351f, 352, 374, 376, 380, 384–388, 390, 392–393

MR sialogram, 86f

nuclear medicine/US/MRI, comparison, 87, 87t scintigraphy (nuclear medicine), 5t, 17t, 38t, 45t,

61–62, 61t, 64t, 83–87, 87t, 271, 301t, 382, 384, 407t, 410, 426

sialography, 5t, 17t, 20, 38t, 61–62, 61t, 64t, 83–86, 87t, 270t, 271, 301t, 386, 407–410, 407t, 408f–409f, 410t, 426

ultrasound (US), 20, 85, 85f, 244 Immunofluorescence assay (IFA), 43–44, 389 Immunoregulation, 255–256 Immunosuppression, 256, 289, 299, 332 India, pSS in, 425–427, 426t

Inflammation

chronic, 78, 121, 161–162, 166, 168, 181, 205, 212, 244–245, 254, 258, 345

focal mononuclear cell, 76–78 by focus score, 77f neurogenic, 156–159

ocular surface, 213

Inflammatory cells and cytokines, 165–168 adhesion molecules, 167

B lymphocytes, 166 chemokines, 166–167 cytokines, 167–168 histopathology, 165 T lymphocytes, 166

Infliximab, 27, 167, 279, 294, 364, 389, 461, 474 Information to patients, 35–55

access to computers, 36

ANA laboratory results, 43–44 ANA detection, 43–44 ANA titer, 43

diagnosis of SS, 44 artificial tears, 46 biologic drugs, 44–46 blepharitis, 47

criteria autoimmune disorders, 37 criteria fibromyalgia, 41t–42t, 43 criteria sceleroderma, 40t–41t, 42 criteria SLE, 39t–40t, 42

criteria SS, 37–38

dental caries, prevention, 47–49 dry and painful mouth, 51–53 future guidelines, 37

ocular treatment, 46

oral candida, prevention, 49–51, 52t–53t types, 36–37

use of internet, 36

written information, 35–36 Initiation phase, 121–122

Innate immunity and interferon pathways, 470 BAFF(BLyS)/BAFF receptor system, 470, 470f peripheral blood mononuclear cells (PBMCs), 470 role of APRIL, 470

Intercellular adhesion molecule-1 (ICAM-1), 167 Interferon (IFN)

BAFF (BLyS), 470

gamma signature, 27–28, 99–100, 167, 211, 474 -inducible genes, 104

inhibition, 464–465

interferon-α, 279, 289, 367, 413, 462 pathways, 74, 97, 99, 470, 472 PBMCs, 470

Interferon regulatory factor 5 (IRF5), 97, 99–100, 99t, 103, 470, 472

Internet, 3–4, 8, 16, 36–37, 286

Interstitial cystitis (IC), 25, 118, 152, 298, 307, 319t, 329 Interstitial lung disease (ILD), 152, 294–295, 339t, 341,

434, 448t, 460

Interstitial nephritis (IN), 22, 28, 74, 152, 298, 303, 304f, 307, 308t, 318, 319t, 333, 338, 338t, 339t, 341, 424, 434

azathioprine or mycophenolic acid, 325 corticosteroids, 325

glomerular disease, 326 hypokalemia, 326

muscle paralysis and respiratory arrest, 326 nephrogenic diabetes insipidus, 326

rituximab, 325

type 1 renal tubular acidosis, 325–326 Interstitial Pneumonitis, see Non-specific interstitial

pneumonitis (NSIP) Israel, SS in, 437–438

allergic manifestations, 438 clinical findings, 437

European Consensus Group classification criteria, 437 IgA in SS, 438

pro-inflammatory cytokines, 438 pSS and sSS, 437

salivary eicosanoids (thromboxane B2 and prostaglandin E2), 438

treatment, 438 Italian study, 67–69, 361 IVIg, 118, 168, 306, 342

J

Jaccoud’s arthropathy, 291, 340

Japanese criteria, 60–63, 61t, 65, 406, 407t Japan, management of dry mouth/eye in, 415–420

autologous serum eye drops, 416 future studies, 419–420 preparation of, 417, 418f research, 417

for Sjogren’s and non-Sjogren’s Syndrome, 418–419

tear components, 416

Juvenile inflammatory arthritis (JIA), 306 Juvenile rheumatoid arthritis (JRA), 306

K

Kawasaki disease, 300, 306

Keratoconjunctivitis sicca (KCS), 29, 37, 60, 61t, 62–63, 78, 152, 183, 199, 205, 208–209, 212–213, 291, 306, 393

Klinefelter syndrome, 24

L

Labial salivary gland biopsy, 63, 75–76, 76f, 78, 83, 384, 427

Lacrimal functional unit (LFU), 203–215 autoimmune cycle, 210f

conjunctival-associated lymphoid tissue (CALT), 206

efferent structures goblet cells, 205

lacrimal glands, 204–205 Meibomian glands, 205

innervation of, 204

loss of ocular surface homeostasis lipids, 212

mucin/lipid/aqueous composition, alterations, 211–212

mucins, 212

pro-inflammatory aqueous component, 212–213 maintenance

hormonal, 205 immunological, 206

in normal and pathological situation, 204 normal ocular surface environment

tear film functions, 206–207

ocular surface immunosuppressive environment, 213–214

pathophysiology of dry eye

loss of hormonal support, 208–209

ocular surface inflammatory cycle, 209–211 SS, 214

tear film

aqueous components, 208 hydrated mucin gel, 207 lipid profile, 207–208

Lacrimal keratoconjunctivitis, 199, 205–206, 209, 211, 213–214

Laryngeal manifestations, 270t, 273f bamboo node, 276–277, 276f laryngopharyngeal reflux (LPR), 275–276 mucus, 275, 275f

reflux symptom index (RSI), 276, 276t treatment, 277

Laryngopharyngeal reflux (LPR), 275–277, 341 Laryngotracheal reflux, 23, 320t, 325

LASIK surgery, 28, 180, 199 La/SSB

apotopes, 137

cellular functions, 135–136 epitope mapping, 136–137 47-kDa phosphoprotein, 135 La48 kDa protein, 136f structural function, 136, 136f See also B-cell epitopes

Leflunomide, 297, 307t, 319t, 321t, 324, 340, 431 Likert rating scale, 361

Lip biopsy, 4, 26, 62, 84, 244, 304, 393, 410, 410t, 427 Lissamine Green, 63, 180, 184, 186 Lymphadenopathy, 114, 152, 270t, 271, 305–306, 318,

321t, 323, 346f, 349, 445t, 447, 448t Lymphocytes

biological therapies, 460 IFN–BAFF–B-lymphocyte axis, 474–477 T and B lymphocytes, 166

Lymphocyte diapedesis, 245f

migration in endothelial cells, 244, 245f signaling molecules, 101 T-/B-lymphocyte hyperactivation, 123

Lymphocytic hypophysitis, 386

Lymphocytic interstitial pneumononitis (LIP), 294, 325 Lymphoepithelial sialadenitis (LESA), 152

Lymphoma and lymphoproliferation, 66t, 272t, 338t, 476t development, 471

diagnosis, 347–348, 348f MALT lymphoma, 346f MALT–SS development

diagnosis, 352

risk factors for, 352 risk factors, 346t

staging/evaluation of treatment response, 348–349 treatmesnt, 349–352

M

Magnetic resonance imaging (MRI), 20, 83–87, 85–86, 86f, 87t, 244, 271, 291, 300, 346f, 349, 351f, 352, 376, 380, 384–388, 390, 392–393

Major histocompatability complex (MHC) region, 100–101, 122, 167, 209, 247, 461

Major salivary gland biopsy, 75 Mannose-binding lectin (MBL), 99t, 100 Mann–Whitney test, 411, 412f

Mean fluorescence intensity (MFI), 65, 360, 362 Medical education and awareness, 457–458 Mental fatigue, 69–70, 360–362, 451, 452t, 453 Mesenteric vasculitis, 326–327

Henoch–Schönlein purpura (HSP), 327 intravenous pulse

methylprednisolone/cyclophosphamide, 326 systemic vasculitis, 327

Methotrexate (MTX), 294, 297–298, 307t, 319t, 321t, 324–325, 329, 339t, 340, 342, 390, 427

Microchimerism, 257

MicroRNAs (miRNAs) biogenesis, 484–485 as biomarkers, 485 characteristics, 485

LIN-14 protein levels, 484 physiological functions, 485

Mikulicz disease or Mikulicz syndrome, 74

Minor salivary gland biopsies, 5t, 17t, 18f, 38t, 61t, 64t, 74f, 301t, 407t, 408f–409f

diagnosis of SS, 6, 63

European and California criteria, 76

focal mononuclear cell inflammation, 76–78 focus scoring, 76–78

labial salivary gland biopsy, 75–76, 76f, 78–79, 204, 409

skin trephine, 75

Mix and match tears, 195, 196t, 199

Moisture chambers/humidifiers/contact lenses, 197

Molecular mimicry, 102–103, 103f, 116, 122–123, 133, 143, 253, 469

Molecular recognition theory, 140

Monoclonal antibody, 95, 253, 279, 347, 460–464, 466, 474–475, 477

Mononeuritis multiplex, 29, 66t, 289–290, 304, 308t, 320t, 449t

Mononuclear cells, 28, 62, 74, 74f, 76, 77f, 78–79, 83, 166, 228, 244, 247–248, 252, 359, 378, 381, 461, 470

Mosaic of autoimmunity, 438

Motor nerve conduction abnormalities, 379 Motor neuropathies, 29, 374, 377, 380–381, 449t Mouth breathing, 406, 413

Movement disorders choreic movements, 386

involuntary muscle contractions, 386 Parkinsonism, 386

Mucins, 22, 24, 51, 153–154, 181, 207, 212, 222, 236, 419

Mucosa-associated lymphoid tissue (MALT) lymphoma Ann Arbor staging system, 346

B-cell lymphomas, 346–347

Borrelia burgdorferi in skin, 346

Chlamydia trachomatis in ocular MALT lymphoma, 346

clinical presentation, 347 enlarged parotid gland, 346f

Helicobacter pylori in gastric MALT lymphoma, 346 MALT–SS development

diagnosis, 350f, 352 of parotid gland, 351f

progression-free survival, 352f risk factors for, 352

rituximab, 347 treatment of

B-cell-directed therapies, 349 cyclophosphamide, 349 guidelines for, 349

low-dose radiotherapy, 351 prednisone, 349

R–CP, 349, 352

rituximab monotherapy, 352 Multidimensional Fatigue Inventory (MFI), 360 Multiple mononeuropathy, 377–379, 382, 390

Multiple sclerosis (MS), 79, 94–95, 168, 305, 320t, 342, 376, 383–385, 387–388, 392–393, 450t, 466

Murine cytomegalovirus (MCMV), 253–254 Muscarinic type 3 receptor (M3R) autoantibodies

acetylcholine (Ach), 117 apoptosis model, 117

autoantibody influencing saliva secretion, 118f ELISA, 117

epitopes, 117 mouse/animal models, 117

muscarinic receptor subtypes (M1–M5), 117 non-organ/organ specific autoimmune diseases, 118

Muscular biopsy, 25

Myalgia, 6, 37, 152, 306, 307t, 318, 323–324, 328, 358–359, 388

Myelitis, 321t, 342, 376–377, 384, 390–393, 450t Myoepithelial sialadenitis (MESA), 152 Myopathy, 323, 377, 382, 391

Myositis, 6, 26, 152, 306, 338t, 350f, 379, 382, 424, 449t Myths/Pearls/Tips, 15–29

N

Nasal (rhinologic) manifestations, 275 Natalizumab (Tysabri), 466

National Institutes of Health (NIH), 7, 456–458, 477 Neonatal lupus syndrome (NLS), 136, 141 Nephritis, see Interstitial nephritis (IN) Neurobiology/hormonal control of lacrimal/salivary

gland function, 151–168 acinar cell, 153–154

inflammatory cells and cytokines, 165–168 adhesion molecules, 167

B lymphocytes, 166 chemokines, 166–167

cytokines, 167–168 histopathology, 165 T lymphocytes, 166

neuropeptides, 154–159

acinotrophic neurogenic stimuli, 154–156 neurogenic inflammation, 156–159

sex steroids, 159–165

adrenal function in SS, 162 in female and male SS, 164

intracrine sex steroids production in pSS and sSS, 164

peripheral intracrine synthesis of sex steroids, 163 putative mechanism of action of intracrine

processing defect, 164–165

regulation of the adrenal steroidogenesis, 161–162 steroidogenesis in adrenal glands, 159–161

Neurological manifestations, 374–395 ANA, 389

autonomic neuropathy, 383 clinical evaluation, 377 CNS manifestations

aseptic meningoencephalitis, 386 cognitive impairment, 385 inflammatory disease, 384 investigations of, 387–388 movement disorders, 385–386 neurological disorders, 386

of fibromyalgia, 388–389 investigations

autonomic studies, 379–380

MR imaging of the spinal cord, 380 neurophysiology, 379–380

neurological and lacrimal/salivary aspects, 394–395 neurologists

demyelinating syndromes, 392–393 neurological/sicca manifestations, relationship,

392–393

neuropathic pain, 391–392 neuromuscular pain, 382 neuromuscular weakness, 381 painful sensory neuropathies, 380 pathogenesis

antibodies, 379

cell-mediated immunity, 377–378 peripheral clinical manifestations, 380–381 rheumatologists, 393

sensory ataxic neuropathy, 380–381 treatment

ataxic neuropathy, 389

central nervous system treatment, 389–390 motor and sensory neuropathies, 390 painful sensory neuropathies, 389

peripheral nervous system treatment, 389–390 side effects of immunosuppressive therapy,

390–391

trigeminal neuropathy and cranial neuropathies, 383 Neurology, 3, 7, 286, 430t

Neuromyelitis optica (NMO, Devic’s syndrome), 384 Neurontin or Lyrica, 54t, 307t, 320t–321t, 391

Neuroparalytic or neurotrophic keratitis, 181 Neuropathy

amyloid, 383 ataxic, 389 autonomic, 484 idiopathic, 374, 388

IgM paraproteinemic, 381 motor, 379

multiple mononeuropathy, 377–379, 382, 390 paraneoplastic autonomic, 383

peripheral, 380, 434 sensory ataxic, 379–381 trigeminal and cranial, 383

Neuropeptides

acinotrophic neurogenic stimuli, 154–156 acetylcholine (black circles), 155, 155f nervous system, importance of, 156 neurotransmitters, 156

reflectory flow, 155

reflex secretory flow, 154–155 VIP release, 156

neurogenic inflammation, 156–159

calcitonin gene-related peptide (CGRP), 157t, 158 neuropeptide Y (NPY), 157t, 158

substance P, 156–158, 157t

vasoactive intestinal peptide (VIP), 157t, 158–159

Neurophysiology, 379–380

EMG/nerve conduction velocity (NCV), 379–380 neurogenic abnormalities, 379

sensory-evoked potentials, 379

sensory nerve action potentials (SNAPs), 379 Neurotransmitter, 26, 117, 154, 156, 157t, 158, 205, 394,

473, 484 Niche theory, 124

Nocturnal hyposalivation, 411

Non-Hodgkin’s lymphoma (NHL), 13, 19f, 74, 114, 274, 289, 294, 352, 423

Non-invasive evaluation of salivary glands, 83–87 Non-specific interstitial pneumonitis (NSIP), 294–295,

298, 307, 319t, 325, 341 Nuclear autoantigen of 14 kDa (NA14)

cytoplasmic organelles (golgins), 119–120 identification, 120

mitotic organelles, 120 prevalence of, 120–121

Nuclear mitotic apparatus protein (NuMA), 112–113

O

Ocular dryness, 5t, 17t, 22, 38t, 279, 293, 330, 364, 366–367, 389, 438, 451, 452t

Ocular gel, 331

Ocular ointment, 309t, 331 Ocular surface

homeostasis, loss of lipids, 212

mucin/lipid/aqueous composition, alterations, 211–212

mucins, 212

pro-inflammatory aqueous component, 212–213

immunosuppressive environment, 213–214 inflammatory cycle, 209–211

afferent arm, 209–211

adoptive transfer models, 210–211 kallikrein 13, 210

osmotic stress, 209

resident corneal dendritic cells, 209 tear osmolarity, 209

autoimmunity, 209 efferent arm, 211

Omeprazole, 278

Ophthalmology, 3, 7, 46, 183, 193, 196t, 286, 430t Optic neuritis, 383–384, 450t

Oral and dental manifestations, 221–239, 231t anti-Ro (SSA) and anti-La (SSB), 274

candida infections—prevention and treatment, 238 complications of oral dryness

caries preventive measures, 233–238 management of xerostomia, 230–233

diagnostic fluid, saliva biomarker analyses, 227–228 exploration of saliva, 228–230

esophageal candidiasis, 272, 273f laryngeal candidiasis, 272, 273f manifestations, 272–274, 272t oral health and disease, saliva in

assessment of oral dryness, 223–226

saliva in dental and mucosal defense, 222–223 oropharyngeal clinical manifestations, 224t persistent glandular enlargement, 274

saliva, 272–273

salivary gland enlargement, 274 xerostomia, 272f

Oral candida

prevention/treatment, 49–51, 52t–53t topical anti-fungal drugs, 52t

Oral candidiasis, 23, 51, 52t, 53t, 238, 291, 324, 340 Oral cavity, 222–223, 228, 237–238, 270, 272–273, 306,

405, 411–413, 412t

Oral medicine, 3, 7, 37, 53, 230, 286 Organ damage criteria, 304, 305t Otolaryngologic manifestations, 269–280

diagnosis, 270–271 MRI and MRS, 271 Oral Allen Test, 271

ORL workup and investigations, 270t parotid:submandibular gland uptake ratio

(P:S ratio), 271 serological tests, 271

ultrasound scoring system (USS), 271 head and neck manifestations

esophageal, 277–279 laryngeal, 275–277, 275f ophthalmic, 272

oral, 272–274 otologic, 274 rhinologic, 275 thyroid, 279

recommendations for SS patients, 280 treatment, 279–280

Otolaryngology, 3, 7, 286

Outcome measures, 65–70, 357–368, 456, 463

P

Painful bladder syndrome (PBS), 329

Painful sensory neuropathies, 377–381, 389, 393 Paraneoplastic autonomic neuropathy, 383 Paraplegia, irreversible, 384

Parasympathetic nerve dysfunction, 382 Parotid biopsy, 75, 271, 348–349 Partial tarsorrhaphy, 192

Pathogen-associated molecular patterns (PAMPs), 247

Patient-reported outcome, 444 Perfusion techniques, 85, 87t Pericarditis, 39t, 295, 302t, 308t, 320t Periodontal disease, 272, 272t, 324, 340

Peripheral blood cell (PBC), 104, 297, 327–328 Peripheral blood mononuclear cells (PBMCs), 359,

470

Peripheral nervous system (PNS), 152, 158, 374, 377, 389–390, 392, 446t, 447, 449t–450t

Peripheral neuropathies, 45t–46t, 66t, 67t, 68t, 305t, 320t, 338t–339t, 446t

autonomic neuropathies, 374, 382 axonal polyneuropathies, 374 cranial neuropathies, 375, 380 ganglionopathies, 375, 380

motor neuropathy or neuromuscular weakness, 380

pseudo-athetosis, 381 sensory neuropathies, 380 small fiber neuropathies, 374 vasculitic neuropathies, 374

Photophobia, 182, 192, 206 Physical fatigue, 362

Physician global assessment of disease activity (PhGA), 447

Pilocarpine (Salagen R ), 154, 197–198, 229, 231t, 235, 251, 279, 366, 405, 410, 416, 424, 429

Piper Fatigue Scale (PFS), 361

Plasmacytoid dendritic cells (pDCs), 105, 167, 244, 254–255, 464, 472f

Pneumocystic or drug pneumonitis, 391 Pneumonitis, see Non-specific interstitial pneumonitis

(NSIP)

Polyneuropathy, 289, 349, 352, 379, 382, 449t–450t Polyradiculoneuropathy, 379, 381

Positron emission tomography (PET), 87 Post-translational modifications (PTMs), 143–144

arginine modifications citrullination, 144 dimethylation, 143–144

serine/threonine phosphorylation, 144 Prednisolone, 66, 198, 308t, 320t–321t, 326, 339t, 341,

386, 446t, 447, 463 Pregabalin, 23, 307t, 320t–321t Premalignant lesions, 152

Preserved tears, 47, 47t, 194–195, 196t, 199

Primary biliary cirrhosis (PBC) complications, 327

deficiencies of fat-soluble vitamins, 327 delayed gastric emptying, 328 gastroparesis, 328

immunosuppressive drugs, 327 medium-chain triglycerides (MCTs), 327 pancreatic insufficiency, 327

pancreatitis and sclerosing cholangitis (PSC), 329 Profile of Fatigue and Discomfort (PROFAD), 65, 67, 69,

359, 362, 444, 451, 452t, 453

Progressive multifocal leukoencephalopathy (PML), 386, 391, 466

Progressive systemic sclerosis, 5t, 17t, 20, 38t, 290, 302t

Protein-losing enteropathy, 434

Protein tyrosine phosphatase non-receptor type-22(PTPN22), 101

Proteomics, 97f

high-throughput transcriptional profiling, 104 studies on salivary gland tissue/saliva, 105 systems biology, 104

transcriptional or gene expression profiling, 104 Pseudo-Sjögren’s syndromes, 152

Pulmonary hypertension, 25, 66t, 294, 306, 308t, 320t, 434

Pulmonary veno-occlusive disease, 333

Pulse intravenous cyclophosphamide, 341–342 Punctal occlusion, 192, 197

Punctal plugs, 66t dry eye, 416 Herrick plug, 197

silicone punctal plugs, 197 temporary punctal occlusion, 197

Q

Quality of life (QOL)

health status/health-related, 363 SF-36 scores, 363

WHOQOL-BREF domains, 363, 363f

R

Raynaud’s phenomenon cutaneous/dermatologic manifestations, 290 dry skin manifestations, 290

extraglandular manifestations, 321 pharmacologic treatment, 323 with primary SS, 323

Recognition phase, 122–123

Recollection of Sjögren’s original patients, 11–13 Recombinant serotype 2 adenoassociated virus vector

(rAAV2), 465 Reflex tearing, 182, 185, 416 Research, 423–424

Rheumatoid arthritis (RA), 5t, 17t, 38t, 44, 62, 79, 94, 111, 152, 164, 168, 244, 269, 277, 291, 294, 306, 318, 323, 338–340, 358–359, 361, 363, 367, 382, 423, 426, 433, 466, 474–475, 485

Rituximab (RTX), 307t–308t, 319t–321t, 350f, 365f, 476t

Australia treatment, 424 B-cell depletion, 462–463 in China, 431–432

CNS manifestations, 393

dryness (sicca) symptoms, 364–366 fatigue, 364

MALT lymphoma, 347

Rose Bengal staining, 63, 183–184, 419f Ro/SSA, 133–145, 228, 393

S

Saliva, 27

collection tests, 15 crisp3 levels, 27

low salivary dehydroepiandrosterone, 27 pH, 27

protein secretions, 27 WS proteins, 27

Saliva in dental/mucosal defense, 222–223 as buffers, 223

glycoproteins, 222–223 microbial species, 222 mucin and enzymes

(lactoferrin/lysozyme/peroxidase), 222 pH in dental biofilm, 223

proteins content and composition, 222 structural function, 222

Salivary flow rates, 20 Salivary gland dysfunction

acinar cell innervation and humoral immunity, 251–252

ACh and substance P, 251

anti-M3R antibodies, 252

NOD Igμnull mice, studies in, 252 fluid movement and AQPs, 252–253 inflammatory mediators, 252

Salivary gland epithelial cell (SGEC) lines, 105, 123, 246–247, 473

Salivary glands

benign lymphoepithelial lesion, 74–75 major salivary gland biopsy in SS, 75

minor salivary gland biopsy in SS, 74f, 75–78 non-invasive evaluation of, 83–87

See also Neurobiology/hormonal control of lacrimal/salivary gland function

Salivary glands, etiology/pathogenesis, 243–258, 246f and immunity of autoimmune diseases

apoptosis/autoantigens/potential danger signals, 254–255

B-cell-activating factor, 256–257 environmental factors, 253–254 hormones, 257 immunoregulation, 255–256 microchimerism, 257

secondary signals, 254 late-breaking additions, 257–258 manifestation of SS

B cells, 250

endothelial cells, 244–245 epithelial cells, 245–247

germinal center-like structure formation, 250–251 lymphoid organization, 250–251

T cells, 247–250 salivary gland dysfunction

acinar cell innervation and humoral immunity, 251–252

fluid movement and aquaporins, 252–253 inflammatory mediators, 252

Salivary MRI, see Magnetic resonance imaging (MRI) Salivary proinflammatory markers, 438

Salivary scintigraphy, see Scintigraphy (nuclear medicine)

Salivary stimulation, 233–234 local salivary stimulation, 234

electrical stimulation, 235

gustatory and/or masticatory stimulation, 234 sugar-free saliva, 235

systemic salivary stimulation, 235 pilocarpine and cevimeline, 235

Salivary substitutes, 236–237 Biotène R , 236

Oral Balance R , 236

Saliva Orthana R , 236 Zendium R , 236

San Diego criteria, 60–62, 61t San Francisco criteria, 60, 61t Saxon test, 20

Schirmer’s-I test, 63

Schirmer’s test, 5t, 22, 38t, 45t, 61t, 62–63, 64t, 65, 66t, 67, 67t, 184–185, 212–213, 270t, 301t, 305t, 367, 384, 407t, 451, 464

Scintigraphy (nuclear medicine), 5t, 18t, 38t, 45t, 61–62, 61t, 64t, 83–87, 87t, 271, 301t, 382, 384, 407t, 410, 426

Sensorineural hearing loss (SNHL), 25, 274 Sensory ataxic neuropathy, 377–379, 380–382 Sensory neuropathies, 320t, 375, 377–382, 390, 393,

449t

Sex steroids, 159–165

adrenal function in SS, 162 cytokines, 162

low systemic levels of DHEA, 162 in female and male SS, 164 intracrine processing defect, 164–165

acinar cell, 165 cellular cloning, 164

progenitor cells, 164–165

intracrine production in pSS and sSS, 164 conversion of DHEA to DHT, 164 periphery cytokines, 164

peripheral intracrine synthesis, 163 classical intracrine tissues, 163 of DHEA-S, 163, 163f intracrinology, 163

regulation of adrenal steroidogenesis, 161–162 aldosterone synthesis, 161

Sex steroids (cont.)

corticosteroid synthesis, 161 DHEA(-S) production, 161–162, 162f

steroidogenesis in adrenal glands, 159–161 corticosteroids, 159–160 corticosteroid synthesis, 160–161, 160f glomerular zone cells, 159 glucocorticosteroids, synthesis of, 160 medulla and cortex, 159

mineralocorticosteroids, synthesis of, 160 prohormones, 159

SF-36 score, 65, 67, 362–363, 363f, 434, 463 Shrinking lung syndrome, 333

Sialadenitis, 5t, 7, 17t, 20, 38t, 62, 64t, 78, 84, 95, 117, 119, 121, 124, 152, 249, 253, 256, 270, 393, 409, 464

Sialectasis, 17t, 38t, 64t, 84, 407

Sialography, 5t, 17t, 20, 38t, 61–62, 61t, 64t, 83–86, 87t, 270t, 271, 301t, 386, 407t, 408f, 409f, 410t, 426

cevimeline treatment, 410

conventional hand-injection method, 409 multiple regression, 410, 410f

parotid gland vs. minor salivary gland, 409–410 pre-treatment and post-treatment WSS, 409 use of pilocarpine, 410

Sialometory, 61, 83–84, 224, 227, 270t, 301t, 407, 408f, 410t

Sicca Symptoms Inventory (SSI), 65, 69, 366, 444, 451, 452t

Signal transduction and activators of transcription (STAT)6-deficient, 249

Sjogren’s Syndrome Foundation (SSF), 37, 455–458 clinical practice guidelines, 456, 458

Facilitator for Both Initiatives, 458 Ocular Working Group, 458

Oral Working Group, 458 Rheumatology Working Group, 458 SSF Clinical Trials Consortium, 458

clinical trials consortium, 456–457 professional education and awareness, 457–458

Slit-lamp biomicroscopy, 182 Somatic fatigue, 362 SONAR, 85

Sporadic amyloid and genetically determined amyloidosis, 383

SS-A/Ro, 112–113, 114f apoptosis, 115–116 B-cell epitope, 116 CHB model, 116

ELISA or immunoblotting, 115 epidemiology, 62

nuclear and nucleolar staining, 113f pathogenesis, 114–115

Ro52 (TRIM21), 114 SLE, 115

tissue destruction mechanism, 116 SS-B/La, 112, 114f

apoptosis, 115–116

B-cell epitope, 116 CHB model, 116

ELISA or immunoblotting, 115 epidemiology, 62 pathogenesis, 114–115

SLE, 115

tissue destruction mechanism, 116

SSclinical activity index (SCAI), 66–67, 69, 359, 444, 445t–446t, 447

SS damage index (SSDI), 66–67, 66t, 69

SS disease activity index (SSDAI), 68–70, 68t, 444, 445t–446t, 447, 448t

SS disease damage index (SSDDI), 67t, 68–69 Standards of Care guidelines, 16

Stenson’s or Wharton’s duct, 271

Substance P, 156, 157t, 158, 205, 211, 251, 416 Sulfasalazine, 324, 340

Sural nerve biopsy, 29, 377, 393 Sweden, 11–13

aerobic exercise/fatigue, 13 clinical features, 12–13 joint/eye symptoms, 13

prevalence/incidence in Scandinavia, 12 Systemic activity

comparisons of scores, 447 ESSDAI, 447, 448t–450t SCAI, 447

SSDAI, 444

Systemic autoimmune disease, 111–112, 119–120, 123–124

Systemic lupus erythematosus (SLE), 19t and autoimmune diseases, 97–98

in China, 431 classification criteria, 42 criteria, 39t–40t, 42

extraglandular manifestations, 300–306, 301t–302t, 304f

in India, 425

pSS/RA/SLE, distinction between, 359 secondary SS, 111

and SS, 21–22, 22f, 300, 301t–302t, 303f SS-A/Ro, 115

SS-B/La, 115

T

T cells, 247–250 Bax/Bcl-2 pathway, 248 CD8+ T-cell, 247 cytokine profiles, 249

glandular destruction and dysfunction, 248f and natural killer (NK) cells, 248

T-cell receptors (TCRs), 248 TH1 and TH2 cells, 249

T helper (TH) cells (CD4+ T cells), 247–248 Treg subsets, 249–250

Tear components, 416 artificial tears, 416

autologous serum eye drops, 416 Punctal plug, 416

secretagogues, 416 Tear film

aqueous components, 208 electrolytes, 208 growth factors, 208

main and accessory lacrimal glands, 208 topical anesthesia, 208

hydrated mucin gel, 207 lipid profile, 207–208

Tear film breakup time, 184

Tear selection, home points for, 199 Technetium-99m-HMPAO SPECT, 388

Technetium 99m Tc-sodium pertechnetate (99mTc-PT), 86

Teeth and saliva, 233–234 fluorides, 233–234, 234f salivary substitutes, 236–237 stimulation, 234–236

Tenacious mucus in eyes, 182

Therapies based on pathogenesis, emerging, 469–478 development of new drugs in pSS

antagonists of BAFF and APRIL, 474–475, 475f Anti-CD20 and Anti-CD22, 477

B-cell depletion, 475–477 Disease Activity Score, 473 IFN blockade, 474 increase of BAFF, 474

inhibition of the triggering factors of IFN activation, 474

selection of patients, 473 of pSS

activation of innate immunity and interferon pathways, 470

autoantibody secretion, 472 BAFF overexpression, 471 breach of self-tolerance, 469–470

cytokines, chemokines, and adhesion molecules, 471–472

glandular hypofunction, 472–473

multiple cellular origins of BAFF, 470–471 regulation of BAFF secretion, 471

therapeutic perspectives gene therapy, 477

inhibition of other cytokines and chemokines, 477 inhibition of T-cell co-stimulation, 477

Thromboembolic disease, 330 Thyroid disease, 24, 27–28, 95, 292 Thyroiditis

autoimmune, 24, 124, 279 Hashimoto’s, 97, 251

Tocilizumab, 466

Toll-like receptors (TLRs), 28, 97, 99, 105, 167, 244, 247, 254, 258, 464, 471–472, 474

Traditional Chinese Medicine (TCM), 432 Traditional Chinese Practitioners (TCPs), 429 Transforming growth factor-beta1 (TGF-β(beta)1),

100

Transnasal esophagoscopy (TNE), 278 Tricylic anti-depressants (TCAs), 391

Trigeminal neuropathy and cranial neuropathies, 383 Tumor necrosis factor (TNF) inhibitor, 26–27, 99t, 100,

102, 116, 122, 125, 157t, 161–162, 164–165, 167–168, 209, 211–213, 247, 253–254, 256, 299, 331, 359, 364, 461–462, 466, 470, 472–475

U

Ultrasound (US), 20, 85, 85f, 244 Unclear and misleading syndromes, 431

Undifferentiated connective tissue disease (UCTD), 42 Unisex organs, 163

University of California, San Francisco (UCSF), 457 Urinary tract symptoms and cystitis, 25

Utility value, 181 Uveitis, 46

V

Vaginal dryness, 329–330

estrogen replacement therapy, 329 lubricants, 329

vaginal atrophy, 330 yeast infection, 330

Vague cognitive dysfunction, 388 Vapor therapy, 275

Vascular cell adhesion molecule (VCAM-1), 167, 244, 247

Vasculitic neuropathies, 374, 382, 424 Vasculitis

classification and diagnosis, 300 CNS arteritis, 300

features, 300 skin lesions, 333

Vasculopathy, 290, 297, 304, 376–378, 384–385, 388 Viruses

autoimmune disease mechanisms, 102 development of autoimmunity, 103, 104f EBV EBNA-1 and Ro epitopes, 103, 104f infectious agents, 102

possible host–environment interactions, 103 See also Genomics and viruses

Visual analog scale (VAS), 65, 69, 293, 361–362, 364, 365f, 366–367, 412, 412t, 463–465, 475, 477

Von Willebrand Factor A (vWFA) domain, 137

W

Wegener’s granulomatosis, 20, 97, 101, 275, 300 Whole resting saliva (WRS) flow, 411

Whole stimulated sialometry (WSS), 407–408, 408f, 409f Workshops, 65, 367, 456–458

X

Xerodent R , 235

Xerophthalmia, 204, 270t, 272, 484

Xerosis, 275, 286, 321–322

Xerostomia, 78

definition, 406

management of, 230–233