Download Literature Review, Clinical Rationale, Evidence Summaries with

Appendix 4 – Inflammatory Musculoskeletal Pain TRG
Literature Review Summaries, Clinical Rationales, and Evidence Summaries
with References
Materials reviewed by the Consensus Expert Panel
Literature Review
Literature searches for DMARDs were conducted in 4 different phases due to the large
number of DMARDS reviewed (Supplementary material – Figure 4). Starting in June 2012, 182
titles were identified for Search #1; 24 articles for Search #2; 294 articles for Search #3; and 532
articles for Search #4. An updated literature search on March 28, 2014 resulted in 18 additional
articles for consideration, and a subsequent search on May 27, 2014 resulted in another 10
articles. In all, 1,060 abstracts were reviewed.
Twelve articles were selected as meeting the TRG's pre-selected criteria for further study (29,
49-50, 56, 58, 77-83); two additional articles that included no therapeutic interventions (84-85)
and seven systematic reviews were also considered (85-91). These latter articles contributed to
the TRG's overall information and subsequent discussion for management and treatment of
inflammatory musculoskeletal pain in Sjögren’s but were not considered as part of the evidence.
Of the twelve publications that met TRG criteria, one covered more than one therapy (78). The
TRG considered six studies on hydroxychloroquine (49, 56, 77-79, 92), three on methotrexate
(78, 80, 93), two on leflunomide (58, 93), and one on azathioprine (50).
Clinical Rationale
Many patients with connective tissue disease, including individuals with primary Sjögren’s,
can suffer from inflammatory joint and muscle pain. Manifestations range from arthralgias and
myalgias to frank synovitis. Musculoskeletal pain may impact a patient’s ability to work and/or
perform normal activities of daily living and, therefore, contributes to overall disease-related
disability. Evaluation and management of this problem are further complicated by the presence
of multiple Sjögren’s-related co-morbidities that may also cause pain including but not limited
to: fibromyalgia, vitamin D deficiency and hypothyroidism. In addition, coincidental age-related
osteoarthritis is common in the middle-aged and older adult Sjögren’s population and further
contributes to pain.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are often utilized as 1st line therapy for
mild pain and/or arthritis but frequently provide incomplete relief and cause multiple side effects
including but not limited to dyspepsia, ulcers, reflux and renal compromise. Disease modifying
antirheumatic drugs (DMARDs), which have proven useful in the management of rheumatoid
arthritis and systemic lupus erythematosus, are commonly used to treat inflammatory
musculoskeletal pain in Sjögren’s. To date, there is no universal agreement on the medication of
choice. Occasionally, these treatments may also cause life-altering or life-threatening side effects
including but not limited to: retinal toxicity, cytopenias and infections. Therapeutic benefit can
only be assessed after consideration of other patient medical problems, severity of pain and the
impact of musculoskeletal pain on physical function and quality of life. Therefore, guidance
regarding the efficacy and safety of DMARD treatment for musculoskeletal pain in Sjögren’s is
needed to help physicians devise a rational treatment algorithm in order to optimize the
benefit/risk ratio at every level of therapy.
Evidence Summary
Evidence Summary: Hydroxychloroquine for Inflammatory Musculoskeletal Pain in
Sjögren’s
The TRG found more studies (seven) for use of hydroxychloroquine in Sjögren’s than for
any other treatment; six met its pre-selected criteria (49,56,77-79, 92). All but one (77)
demonstrated benefit of HCQ at least at some level.
Fauchais et al (78) concluded that 75% of Sjögren’s patients showed symptomatic
improvement with HCQ. This study involved a large sample size with excellent follow-up and
measured joint pain, tenderness and swelling as primary outcomes; however, no controls or
placebo were used, and methods of assessment were not detailed. In a second study with large
enrollment but no controls or placebo (R Fox et al 1996) (57), HCQ significantly improved
stiffness, myalgias, arthralgias, joint swelling, ESR and IgG in most patients. An earlier study by
R Fox et al in 1988 (79) also showed significant improvement in IgG, IgA, IgA, RF, anti-SSB,
ESR, and Hgb over 12 months compared to untreated controls. Mumcu et al (2013) (92) found
higher serum and salivary BAFF levels in Sjögren’s patients compared to controls, and that
patient levels of BAFF were significantly lowered with HCQ treatment at both 12 and 24 weeks
compared to pre-treatment baseline. Two studies reported little to no benefit: One of these
studies, by Kruize et al (1993) (50) found no clinical improvement but noted decreases in levels
of IgG and IgM and a slight decrease in ESR. In a randomized, controlled, trial Gottenberg et al
(2014) (77) found no significant difference in the proportion of patients (HCQ n=52, placebo
n=53) with reduction in pain, fatigue or dryness at the primary end point of 24 weeks (HCQ
17.2% vs. placebo 17.9%). When all patients were treated with HCQ from 24-48 weeks some
separation between the two groups was noted (HCQ 30.4% vs. placebo/HCQ 18.8%) (p= 0.21).
Evidence: Methotrexate
The strongest study on the use of methotrexate (MTX) for inflammatory musculoskeletal
pain in Sjögren’s by Fauchais et al (2010) (78) was uncontrolled but demonstrated a good
clinical response. Articular manifestations improved in 11 out of 12 Sjögren’s patients on MTX
compared to pre-treatment baseline. For the remaining two studies, one (Skopouli FN et al) (80)
found a decrease in the frequency of arthralgias in 80% (8/10) of Sjögren’s patients with
inflammatory musculoskeletal pain at 6 months and 40% (4/10) at 12 months. A second
observational case study (Khan and Carsons) (93) that described six primary Sjögren’s patients
whose course was complicated by the development of nonerosive rheumatoid arthritis, reported
benefit from the use of DMARDs (MTX or leflunomide) with or without biological therapy.
Evidence: Leflunomide
Two studies were found using leflunomide for inflammatory musculoskeletal pain in
Sjögren’s that met pre-determined criteria for consideration. The first, van Woerkom et al (2007)
(58) was an open-label phase 2 pilot study that showed modest efficacy in primary Sjögren’s
patients. The study demonstrated improvement in lip biopsy focuses scores, fatigue, physical
functioning, IgG levels and leukocytoclastic vasculitis, but had no MSK endpoint. The safety
profile was considered acceptable. The second study, Khan and Carsons (93), was an
observational study of six primary Sjögren’s patients with aggressive arthritis and subsequent
diagnosis of RA that required the use of DMARDs (MTX or leflunomide) with or without
biological therapy. Both studies noted that the primary adverse symptoms with use of
leflunomide were diarrhea and gastrointestinal discomfort.
References for Supplementary Materials –
All Literature Review, Clinical Rationale, and Evidence Summaries
14. Dass S, Bowman SJ, Vital EM, Ikeda K, Pease CT, Hamburger J, Richards A, Rauz S, Emery P.
Reduction of fatigue in Sjögren syndrome with rituximab: results of a randomised, double-blind, placebocontrolled pilot study. Ann Rheum Dis. 2008 Nov;67(11):1541-4.
15.Devauchelle-Pensec V, Pennec Y, Morvan J, Pers JO, Daridon C, Jousse-Joulin S, Roudaut A, Jamin
C, Renaudineau Y, Roué IQ, Cochener B, Youinou P, Saraux A. Improvement of Sjögren's syndrome
after two infusions of rituximab (anti-CD20). Arthritis Rheum. 2007 Mar 15;57(2):310-7.
16.Meijer JM, Meiners PM, Huddleston Slater JJ, Spijkervet FK, Kallenberg CG, Vissink A, Bootsma H.
Treatment of primary Sjogren syndrome with rituximab: extended follow-up, safety and efficacy of
retreatment. Ann Rheum Dis. 2009 Feb;68(2):284-5.
17.Meijer JM, Meiners PM, Vissink A, Spijkervet FK, Abdulahad W, Kamminga N, Brouwer E,
Kallenberg CG, Bootsma H. Effectiveness of rituximab treatment in primary Sjögren's syndrome: a
randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010 Apr;62(4):960-8.
18.Pijpe J, van Imhoff GW, Vissink A, van der Wal JE, Kluin PM, Spijkervet FK, Kallenberg CG,
Bootsma H. Rituximab treatment in patients with primary Sjögren's syndrome: an open-label phase II
study. Arthritis Rheum. 2005 Sep;52(9):2740-50.
19.Seror R, Sordet C, Guillevin L, Hachulla E, Masson C, Ittah M, Candon S, Le Guern V, Aouba A,
Sibilia J, Gottenberg JE, Mariette X. Tolerance and efficacy of rituximab and changes in serum B cell
biomarkers in patients with systemic complications of primary Sjögren's syndrome. Ann Rheum Dis.
2007 Mar;66(3):351-7.
20.Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, Berthelot JM, Perdriger A, Puéchal X, Le Guern
V, Sibilia J, Gottenberg JE, Chiche L, Hachulla E, Hatron PY, Goeb V, Hayem G, Morel J, Zarnitsky C,
Dubost JJ, Pers JO, Nowak E, Saraux A. Treatment of primary Sjögren syndrome with rituximab: a
randomized trial. Ann Intern Med. 2014 Feb 18;160(4):233-42.
21.Sankar V, Brennan MT, Kok MR, Leakan RA, Smith JA, Manny J, Baum BJ, Pillemer SR. Etanercept
in Sjögren's syndrome: a twelve-week randomized, double-blind, placebo-controlled pilot clinical trial.
Arthritis Rheum. 2004 Jul;50(7):2240-5.
22.Mariette X, Ravaud P, Steinfeld S, Baron G, Goetz J, Hachulla E, Combe B, Puéchal X, Pennec Y,
Sauvezie B, Perdriger A, Hayem G, Janin A, Sibilia J. Inefficacy of infliximab in primary Sjögren's
syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjögren's Syndrome
(TRIPSS). Arthritis Rheum. 2004 Apr;50 (4):1270-6.
23.Zandbelt MM, de Wilde P, van Damme P, Hoyng CB, van de Putte L, van den Hoogen F. Etanercept
in the treatment of patients with primary Sjögren's syndrome: a pilot study. J Rheumatol. 2004
Jan;31(1):96-101.
24.Jousse-Joulin S, Devauchelle-Pensec V, Morvan J, Guias B, Pennec Y, Pers JO, Daridon C, Jamin C,
Renaudineau Y, Roué IQ, Cochener B, Bressollette L, Youinou P, Saraux A. Ultrasound assessment of
salivary glands in patients with primary Sjögren's syndrome treated with rituximab: Quantitative and
Doppler waveform analysis. Biologics. 2007 Sep;1(3):311-9.
25.Mekinian A, Ravaud P, Hatron PY, Larroche C, Leone J, Gombert B, Hamidou M, Cantagrel A,
Marcelli C, Rist S, Breban M, Launay D, Fain O, Gottenberg JE, Mariette X. Efficacy of rituximab in
primary Sjögren’s syndrome with peripheral nervous system involvement: results from the AIR registry.
Ann Rheum Dis. 2012 Jan;71(1):84-7.
26.Gorson KC, Natarajan N, Ropper AH, Weinstein R. Rituximab treatment in patients with IVIgdependent immune polyneuropathy: a prospective pilot trial. Muscle Nerve. 2007 Jan;35(1):66-9.
27.Ramos-Casals M, García-Hernández FJ, de Ramón E, Callejas JL, Martínez-Berriotxoa A, Pallarés L,
Caminal-Montero L, Selva-O'Callaghan A, Oristrell J, Hidalgo C, Pérez-Alvarez R, Micó ML, Medrano
F, Gómez de la Torre R, Díaz-Lagares C, Camps M, Ortego N, Sánchez-Román J; BIOGEAS Study
Group. Off-label use of rituximab in 196 patients with severe, refractory systemic autoimmune diseases.
Clin Exp Rheumatol. 2010 Jul-Aug;28(4):468-76.
28.St Clair EW, Levesque MC, Prak ET, Vivino FB, Alappatt CJ, Spychala ME, Wedgwood J,
McNamara J, Moser Sivils KL, Fisher L, Cohen P; Autoimmunity Centers of Excellence. Rituximab
therapy for primary Sjögren's syndrome: an open-label clinical trial and mechanistic analysis. Arthritis
Rheum. 2013 Apr;65(4):1097-106.
29.Gottenberg JE, Cinquetti G, Larroche C, Combe B, Hachulla E, Meyer O, Pertuiset E, Kaplanski G,
Chiche L, Berthelot JM, Gombert B, Goupille P, Marcelli C, Feuillet S, Leone J, Sibilia J, Zarnitsky C,
Carli P, Rist S, Gaudin P, Salliot C, Piperno M, Deplas A, Breban M, Lequerre T, Richette P, Ghiringhelli
C, Hamidou M, Ravaud P, Mariette X; Club Rhumatismes et Inflammations and the French Society of
Rheumatology. Efficacy of rituximab in systemic manifestations of primary Sjogren's syndrome: results
in 78 patients of the AutoImmune and Rituximab registry. Ann Rheum Dis. 2013 Jun;72(6):1026-31.
30.Covelli M, Lanciano E, Tartaglia P, Grattagliano V, Angelelli G, Atzeni F, Sarzi-Puttini P, Lapadula
G. Rituximab treatment for Sjögren’s syndrome-associated non-Hodgkin's lymphoma: case series.
Rheumatol Int. 2012 Oct;32(10):3281-4.
31.Voulgarelis M, Giannouli S, Anagnostou D, Tzioufas AG. Combined therapy with rituximab plus
cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) for Sjögren's syndrome-associated B-cell
aggressive non-Hodgkin's lymphomas. Rheumatology (Oxford). 2004 Aug;43(8):1050-3.
32.Devauchelle-Pensec V, Morvan J, Rat AC, Jousse-Joulin S, Pennec Y, Pers JO, Jamin C, Renaudineau
Y, Quintin-Roué I, Cochener B, Youinou P, Saraux A. Effects of rituximab therapy on quality of life in
patients with primary Sjögren's syndrome. Clin Exp Rheumatol. 2011 Jan-Feb;29(1):6-12.
33.Botez SA, Herrmann DN. Prolonged remission of a demyelinating neuropathy in a patient with
lymphoma and Sjögren's syndrome after Rituximab therapy. J Clin Neuromuscul Dis. 2010
Mar;11(3):127-31.
34.Guzman Moreno R. B-cell depletion in autoimmune diseases. Advances in autoimmunity. Autoimmun
Rev. 2009 Jun;8(7):585-90.
35.Rueda JC, Duarte-Rey C, Casas N. Successful treatment of relapsing autoimmune pancreatitis in
primary Sjögren's syndrome with rituximab: report of a case and review of the literature. Rheumatol Int.
2009 Oct;29(12):1481-5.
36.Galarza C, Valencia D, Tobón GJ, Zurita L, Mantilla RD, Pineda-Tamayo R, Rojas-Villarraga A,
Rueda JC, Anaya JM. Should rituximab be considered as the first-choice treatment for severe
autoimmune rheumatic diseases? Clin Rev Allergy Immunol. 2008 Feb;34(1):124-8.
37. Sève P, Gachon E, Petiot P, Stankovic K, Charhon A, Broussolle C. Successful treatment with
rituximab in a patient with mental nerve neuropathy in primary Sjögren's syndrome. Rheumatol Int. 2007
Dec;28(2):175-7.
38.Yamout B, El-Hajj T, Barada W, Uthman I. Successful treatment of refractory neuroSjogren with
Rituximab. Lupus. 2007;16(7):521-3.
39.Ring T, Kallenbach M, Praetorius J, Nielsen S, Melgaard B. Successful treatment of a patient with
primary Sjögren's syndrome with Rituximab. Clin Rheumatol. 2006 Nov;25(6):891-4.
40.Gottenberg JE, Guillevin L, Lambotte O, Combe B, Allanore Y, Cantagrel A, Larroche C, Soubrier M,
Bouillet L, Dougados M, Fain O, Farge D, Kyndt X, Lortholary O, Masson C, Moura B, Remy P, Thomas
T, Wendling D, Anaya JM, Sibilia J, Mariette X; Club Rheumatismes et Inflammation (CRI). Tolerance
and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases. Ann Rheum Dis.
2005 Jun;64(6):913-20.
41.Somer BG, Tsai DE, Downs L, Weinstein B, Schuster SJ; American College of Rheumatology ad hoc
Committee on Immunologic Testing Guidelines. Improvement in Sjögren's syndrome following therapy
with rituximab for marginal zone lymphoma. Arthritis Rheum. 2003 Jun 15;49(3):394-8.
42.Touma Z, Sayad J, Arayssi T. Successful treatment of Sjögren’s syndrome with rituximab. Scand J
Rheumatol. 2006 Jul-Aug;35(4):323-5.
43.Carubbi F, Cipriani P, Marrelli A, Benedetto P, Ruscitti P, Berardicurti O, Pantano I, Liakouli V,
Alvaro S, Alunno A, Manzo A, Ciccia F, Gerli R, Triolo G, Giacomelli R. Efficacy and safety of
rituximab treatment in early primary Sjögren's syndrome: a prospective, multi-center, follow-up study.
Arthritis Res Ther. 2013 Oct 30;15(5):R172.
44.Ng WF, Bowman SJ. Primary Sjogren’s syndrome: too dry and too tired. Rheumatology (Oxford).
2010 May;49(5):844-53.
45.Thanous-Stavraki A, James JA. Primary Sjogren's syndrome: current and prospective therapies. Semin
Arthritis Rheum. 2008 Apr;37(5):273-92.
46.Saraux A. The point on the ongoing B-cell depleting trials currently in progress over the world in
primary Sjogren’s syndrome. Autoimmun Rev. 2010 Jul;9(9):609-14.
47.Ramos-Casals M, Tzioufas AG, Stone JH, Sisó A, Bosch X.Treatment of primary Sjogren's syndrome:
a systematic review. JAMA. 2010 Jul 28;304(4):452-60.
48.Norheim KB, Harboe E, Gøransson LG, Omdal R. Interleukin-1 inhibition and fatigue in primary
Sjögren's syndrome--a double blind, randomised clinical trial. PLoS One. 2012;7(1):e30123.
49.Kruize AA, Hené RJ, Kallenberg CG, van Bijsterveld OP, van der Heide A, Kater L, Bijlsma JW.
Hydroxychloroquine treatment for primary Sjögren's syndrome: a two year double blind crossover trial.
Ann Rheum Dis. 1993 May;52(5):360-4.
50.Price EJ, Rigby SP, Clancy U, Venables PJ. A double blind placebo controlled trial of azathioprine in
the treatment of primary Sjögren's syndrome. J Rheumatol. 1998 May;25(5):896-9.
51.Virkki LM, Porola P, Forsblad-d'Elia H, Valtysdottir S, Solovieva SA, Konttinen YT.
Dehydroepiandrosterone (DHEA) substitution treatment for severe fatigue in DHEA-deficient patients
with primary Sjögren's syndrome. Arthritis Care Res (Hoboken). 2010 Jan 15;62(1):118-24.
52.Hartkamp A, Geenen R, Godaert GL, Bootsma H, Kruize AA, Bijlsma JW, Derksen RH. Effect of
dehydroepiandrosterone administration on fatigue, well-being, and functioning in women with primary
Sjogren syndrome: a randomised controlled trial. Ann Rheum Dis. 2008 Jan;67(1):91-7.
53.Seitsalo H, Niemelä RK, Marinescu-Gava M, Vuotila T, Tjäderhane L, Salo T. Effectiveness of lowdose doxycycline (LDD) on clinical symptoms of Sjögren's syndrome: a randomized, double-blind,
placebo controlled cross-over study. J Negat Results Biomed. 2007 Dec 31;6:11.
54.Gescuk B, Wu AJ, Whitcher JP, Daniels TE, Lund S, Fye K, Davis JC Jr. Lamivudine is not effective
in primary Sjögren's syndrome. Ann Rheum Dis. 2005 Sep;64(9):1326-30.
55.Tishler M, Yaron I, Shirazi I, Yaron M. Hydroxychloroquine treatment for primary Sjögren’s
syndrome: its effect on salivary and serum inflammatory markers. Ann Rheum Dis 1999 Apr;58(4):253-6.
56.Fox RI, Dixon R, Guarrasi V, Krubel S. Treatment of primary Sjögren's syndrome with
hydroxychloroquine: a retrospective, open-label study. Lupus . 1996 Jun; 5 Suppl 1:S31-6.
57.Steinfeld SD, Tant L, Burmester GR, Teoh NK, Wegener WA, Goldenberg DM, Pradier O.
Epratuzumab (humanised anti-CD22 antibody) in primary Sjögren's syndrome: an open-label phase I/II
study. Arthritis Res Ther. 2006;8(4):R129.
58.van Woerkom JM, Kruize AA, Geenen R, van Roon EN, Goldschmeding R, Verstappen SM, van
Roon JA, Bijlsma JW. Safety and efficacy of leflunomide in primary Sjögren's syndrome: a phase II pilot
study. Ann Rheum Dis. 2007 Aug;66(8):1026-32.
59.Steinfeld SD, Demols P, Van Vooren JP, Cogan E, Appelboom T. Zidovudine in primary Sjögren's
syndrome. Rheumatology (Oxford). 1999 Sep;38(9):814-7.
60.Willeke P, Schlüter B, Becker H, Schotte H, Domschke W, Gaubitz M. Mycophenolate sodium
treatment in patients with primary Sjögren syndrome: a pilot trial. Arthritis Res Ther. 2007;9(6):R115.
61.Meiners PM, Vissink A, Kroese FG, Spijkervet FK, Smitt-Kamminga NS, Abdulahad WH, BulthuisKuiper J, Brouwer E, Arends S, Bootsma H. Abatacept treatment reduces disease activity in early primary
Sjögren's syndrome (open-label proof of concept ASAP study). Ann Rheum Dis. 2014 Jul;73(7):1393-6.
62.Mariette X, Seror R, Quartuccio L, Baron G, Salvin S, Fabris M, Desmoulins F, Nocturne G, Ravaud
P, De Vita S. Efficacy and safety of belimumab in primary Sjogren's syndrome: results of the BELISS
open-label phase II study. Ann Rheum Dis. 2015 Mar;74(3):526-31.
63.Theander E, Horrobin DF, Jacobsson LT, Manthorpe R. Gammalinolenic acid treatment of fatigue
associated with primary Sjögren's syndrome. Scand J Rheumatol. 2002;31(2):72-9.
64.Strömbeck BE, Theander E, Jacobsson LT. Effectiveness of exerise on aerobic capacity and fatigue in
women with primary Sjogren's syndrome. Rheumatology (Oxford). 2007 May;46 (5):868-71.
65.Segal B. Fatigue in Primary Sjogren's syndrome. In: Ramos-Casals M, editor. Sjogren's syndrome:
Diagnosis and Therapeutics. London: Springer Verlag; 2012. p. 129-43.
66.Giles I, Isenberg D. Fatigue in primary Sjogren's syndrome: is there a link with the fibromyalgia
syndrome? Ann Rheum Dis. 2000 Nov;59(11):875-8.
67.Segal B, Thomas W, Rogers T, Leon JM, Hughes P, Patel D, Patel K, Novitzke J, Rohrer M,
Gopalakrishnan R, Myers S, Nazmul-Hossain A, Emamian E, Huang A, Rhodus N, Moser K. Prevalence,
severity, and predictors of fatigue in subjects with primary Sjögren's syndrome. Arth Rheum. 2008 Dec
15;59(12):1780-7.
68.Meijer JM, Meiners PM, Huddleston Slater JJ, Spijkervet FK, Kallenberg CG, Vissink A, Bootsma H.
Health-related quality of life, employment and disability in patients with Sjogren's syndrome.
Rheumatology (Oxford). 2009 Sep;48(9):1077-82.
69.Sjögren’s Syndrome Foundation Breakthrough Goal Survey. Polaris Marketing Research, Inc. 2012.
70.Mishra R, Vivino FB. Diagnosis and Management of Fatigue. In: Wallace DJ, editor. The Sjögren’s
Book. The Sjögren’s Syndrome Foundation and Oxford University Press, New York; 2012. p. 228-34.
71.Tench CM, McCarthy J, McCurdie I, White PD, D'Cruz DP. Fatigue in systemic lupus erythematosus:
a randomized controlled trial of exercise. Rheumatology (Oxford). 2003 Sep;42(9):1050-4.
72.Robb-Nicholson LC, Daltroy L, Eaton H, Gall V, Wright E, Hartley LH, Schur PH, Liang MH. Effects
of aerobic conditioning in lupus fatigue: a pilot study. Br J Rheumatol. 1989Dec;28(6):500-5.
73.Carvalho MR, Sato EI, Tebexreni AS, Heidecher RT, Schenkman S, Neto TL. Effects of supervised
cardiovascular training program on exercise tolerance, aerobic capacity, and quality of life in patients
with systemic lupus erythematosus. Arthritis Rheum. 2005 Dec 15;53(6):838-44.
74.Neuberger GB, Press AN, Lindsley HB, Hinton R, Cagle PE, Carlson K, Scott S, Dahl J, Kramer B.
Effects of exercise on fatigue, aerobic fitness, and disease activity measures in persons with rheumatoid
arthritis. Res Nurs Health. 1997 Jun;20 (3):195-204.
75.Neill J, Belan I, Ried K. Effectiveness of non-pharmacological interventions for fatigue in adults with
multiple sclerosis, rheumatoid arthritis, or systemic lupus erythematosus: a systematic review. J Adv
Nurs. 2006 Dec;56(6):617-35.
76.Gutierrez EG, Banks WA, Kastin AJ. Blood-borne interleukin-1 receptor antagonist crosses the bloodbrain barrier. J Neuroimmunol. 1994 Dec;55(2):153-60.
77.Gottenberg JE, Ravaud P, Puéchal X, Le Guern V, Sibilia J, Goeb V, Larroche C, Dubost JJ, Rist S,
Saraux A, Devauchelle-Pensec V, Morel J, Hayem G, Hatron P, Perdriger A, Sene D, Zarnitsky C,
Batouche D, Furlan V, Benessiano J, Perrodeau E, Seror R, Mariette X. Effects of hydroxychloroquine on
symptomatic improvement in primary Sjögren syndrome: the JOQUER randomized clinical trial. JAMA.
2014 Jul 16;312(3):249-58.
78.Fauchais AL, Ouattara B, Gondran G, Lalloué F, Petit D, Ly K, Lambert M, Launay D, Loustaud-Ratti
V, Bezanahari H, Liozon E, Hachulla E, Jauberteau MO, Vidal E, Hatron PY. Articular manifestations in
primary Sjögren's syndrome: clinical significance and prognosis of 188 patients. Rheumatology (Oxford).
2010 Jun;49(6):1164-72.
79.Fox RI, Chan E, Benton L, Fong S, Friedlaender M, Howell FV. (1988). Treatment of primary
Sjögren's syndrome with hydroxychloroquine. Am J Med. 1988 Oct 14;85(4A):62-7.
80.Skopouli FN, Jagiello P, Tsifetaki N, Moutsopoulos HM. (1996). Methotrexate in primary Sjögren's
syndrome. Clin Exp Rheumatol. 1996 Sep-Oct;14(5):555-8.
81.Nakagawa N, Osanai S, Ide H, Nishigaki Y, Takahashi S, Nakano H, Ohsaki Y, Kikuchi K, Tokusashi
Y, Obata H. Severe pulmonary hypertension associated with primary Sjögren's syndrome. Intern Med.
2003 Dec;42(12):1248-52.
82.Sakamoto O, Saita N, Ando M, Kohrogi H, Suga M, Ando M. Two cases of Sjögren's syndrome with
multiple bullae. Intern Med. 2002 Feb;41(2):124-8.
83.Mochizuki H, Kamakura K, Masaki T, Hirata A, Nakamura R, Motoyoshi K. Motor dominant
neuropathy in Sjögren's syndrome: report of two cases. Intern Med. 2002 Feb;41(2):142-6.
84.Lodde BM, Sankar V, Kok MR, Leakan RA, Tak PP, Pillemer SR. Serum lipid levels in Sjögren's
syndrome. Rheumatology (Oxford). 2006 Apr;45(4):481-4.
85.Iannuccelli C, Spinelli FR, Guzzo MP, Priori R, Conti F, Ceccarelli F, Pietropaolo M, Olivieri M,
Minniti A, Alessandri C, Gattamelata A, Valesini G, Di Franco M. Fatigue and widespread pain in
systemic lupus erythematosus and Sjögren's syndrome: symptoms of the inflammatory disease or
associated fibromyalgia? Clin Exp Rheumatol. 2012 Nov-Dec;30(6 Suppl 74):117-21.
86.Winzer M, Aringer M. Use of methotrexate in patients with systemic lupus erythematosus and primary
Sjögren's syndrome. Clin Exp Rheumatol. 2010 Sep-Oct;28(5 Suppl 61):S156-9.
87.Venables PJ. Management of patients presenting with Sjögren’s syndrome. Best Pract Res Clin
Rheumatol. 2006 Aug;20(4):791-807.
88.Fox RI. Sjögren's syndrome: current therapies remain inadequate for a common disease. Expert Opin
Investig Drugs. 2000 Sep;9(9):2007-16.
89.Brito-Zerón P, Sisó-Almirall A, Bové A, Kostov BA, Ramos-Casals M. Primary Sjögren syndrome: an
update on current pharmacotherapy options and future directions. Expert Opin Pharmacother. 2013
Feb;14(3):279-89.
90.Wu JJ, Carsons SE. Management of extraglandular manifestations of primary Sjögren's syndrome.
Oral Maxillofac Surg Clin North Am. 2014 Feb; 26(1):101-9.
91.Tincani A, Andreoli L, Cavazzana I, Doria A, Favero M, Fenini MG, Franceschini F, Lojacono A,
Nascimbeni G, Santoro A, Semeraro F, Toniati P, Shoenfeld Y. Novel aspects of Sjögren's syndrome in
2012. BMC Med. 2013 Apr 4; 11:93.
92.Mumcu G, Biçakçigil M, Yilmaz N, Ozay H, Karaçayli U, Cimilli H, Yavuz S. Salivary and serum Bcell activating factor (BAFF) levels after hydroxychloroquine treatment in primary Sjögren's syndrome.
Oral Health Prev Dent. 2013;11(3):229-34.
93.Khan O, Carsons S. Occurrence of rheumatoid arthritis requiring oral and/or biological diseasemodifying antirheumatic drug therapy following a diagnosis of primary Sjögren syndrome. J Clin
Rheumatol. 2012 Oct;18(7):356-8.
94.Foulks GN, Forstot SL, Donshik PC, Forstot JZ, Goldstein MH, Lemp MA, Nelson JD, Nichols KK,
Pflugfelder SC, Tanzer JM, Asbell P, Hammitt K, Jacobs DS. Clinical Guidelines for Management of Dry
Eye Associated with Sjögren Disease. Ocul Surf. 2015 Apr; 13(2):118-32.