Treatment of primary Sjogrensyndrome with rituximab: extendedfollow-up, safety and efficacy ofretreatment

We previously reported that B cell depletion therapy withrituximab (4 weekly infusions of 375 mg/m2, premedication:25 mg prednisolone intravenously) in eight patients with earlyprimary Sjogren syndrome (pSS) and seven patients withmucosa-associated lymphatic tissue (MALT)/pSS was effectivein reducing subjective and objective symptoms after 12 weeksof follow-up.1 Three patients with early pSS developed serumsickness-like disease, of whom one patient declined to furtherparticipate. The MALT component of six of the seven patientswith MALT/pSS was initially effectively treated with ritux-imab, one of these six patients was successfully retreated9 months after the first treatment and all six patients are still inremission of MALT .2 years after treatment. Therefore, wefocused the present work on the extended follow-up andretreatment of the patients with early pSS. For seven of theeight patients with early pSS, 48-week follow-up data wereavailable. In addition, five patients, who did not develop serumsickness and in whom symptoms returned, were retreated withfour infusions of rituximab and followed for another 48 weeks.Return of symptoms included decrease of salivary flow, increaseof rheumatoid factor and return of B cells and subjectivesymptoms.

First course of rituximab (n = 7)Depletion of peripheral B cells was complete 5 weeks after onsetof therapy. By 36 weeks, median peripheral B cell numbers hadreturned, although levels were still low in some patients.Stimulated submandibular/sublingual salivary flow showed asignificant increase at week 12, followed by a gradual decline tojust above baseline at 48 weeks. Similarly, a significantimprovement of most of the visual analogue scale (VAS) scoresfor dry mouth and most domains of the MultidimensionalFatigue Inventory (MFI) was observed, followed by a gradualdecline to near baseline.

Retreatment with rituximab (n = 5, fig 1)Retreatment had a significant effect on B cells, levels of IgM-rheumatoid factor (RF) and stimulated submandibular/sublin-gual salivary flow similar to the effects of the first course. VASscores for dry mouth, MFI scores for general fatigue and Short-Form 36 (SF-36) questionnaire scores for physical functioningimproved significantly too. For the other subjective symptoms asimilar trend towards improvement was seen as after the firstcourse. Again, almost all variables had returned to baseline 6–9 months after retreatment. One patient developed serumsickness-like disease (purpura, arthralgia, myalgia) after thesecond rituximab infusion during the retreatment course.Rituximab treatment was stopped, pain relief (non-steroidalanti-inflammatory drugs (NSAIDs)) and 120 mg methylpredni-solone was given once. The patient recovered completely.

CONCLUSIONSRituximab appeared to be effective for at least 6–9 months inpatients with pSS with active disease, improving subjective and

objective symptoms. Development of serum sickness-likedisorder in a substantial number of patients with pSS indicatesthat higher doses of corticosteroids might be needed duringtreatment. Retreatment resulted in a good clinical response inpatients with pSS comparable to the response in patients withrheumatoid arthritis (RA)2 and patients with systemic lupuserythaematosus (SLE).3 Based on these promising results, onemight consider maintenance treatment. The best approach toand timing of maintenance treatment has, however, to bestudied in future trials. Furthermore, attention has to be paid toamong others the possibility of development of humoralimmunodeficiency related to repeated treatment.2

J M Meijer,1 J Pijpe,1 A Vissink,1 C G M Kallenberg,2 H Bootsma2

1 Departments of Oral and Maxillofacial Surgery, University Medical Center Groningen,University of Groningen, Groningen, The Netherlands; 2 Departments of Rheumatologyand Clinical Immunology, University Medical Center Groningen, University of Groningen,Groningen, The Netherlands

Correspondence to: J M Meijer, Department of Oral and Maxillofacial Surgery,University Medical Center Groningen, PO-Box 30.001, 9700 RB Groningen, TheNetherlands; j.m.meijer@kchir.umcg.nl

Competing interests: None declared.

Ethics approval: Ethics approval was obtained.

Accepted 9 April 2008

Ann Rheum Dis 2009;68:284–285. doi:10.1136/ard.2008.092601

Figure 1 Increase and decrease (mean values of five patients withprimary Sjogren syndrome (pSS)) in stimulated submandibular/sublingualflow rate, IgM-rheumatoid factor (RF), B cells, visual analogue scale(VAS) score for dry mouth during the night and Multidimensional FatigueInventory (MFI) score for fatigue following rituximab (re)treatment(baseline is 100%). Mean (SD) baseline values (week 0 first treatment)were: stimulated submandibular/sublingual flow rate 0.09 (0.07) ml/min,IgM-RF 339 (329) lU/ml, B cells 0.19 (0.09) 109/litre, VAS score for drymouth during the night 85 (12), MFI score for fatigue 16 (3). N Stimulatedsubmandibular/sublingual salivary flow rate. ¤ IgM-RF. * B cells. m VASscore for dry mouth during the night. . MFI score for fatigue.

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REFERENCES1. Pijpe J, van Imhoff GW, Spijkervet FKL, Roodenburg JLN, Wolbink GJ,

Mansour K, et al. Rituximab treatment in patients with primarySjogren’s syndrome: an open-label phase II study. Arthritis Rheum2005;52:2740–50.

2. Popa C, Leandro MJ, Cambridge G, Edwards JC. Repeated B lymphocyte depletion withrituximab in rheumatoid arthritis over 7 yrs. Rheumatology (Oxford) 2007;46:626–30.

3. Smith KG, Jones RB, Burns SM, Jayne DR. Long-term comparison of rituximabtreatment for refractory systemic lupus erythematosus and vasculitis: remission,relapse, and re-treatment. Arthritis Rheum 2006;54:2970–82.

Interleukin 6 and its soluble receptorin a central role at theneuroimmunoendocrine interface inSjogren syndrome: an explanatoryinterventional study

Sjogren syndrome (SS) is characterised by focal adenitis andfatigue, the latter often the most important symptom.1 Hostreactions and responses to disease and disease-associated fatigueconsists of stimulation of cytokine network, which involvestumour necrosis factor (TNF)a and interleukin (IL)1b, with IL6often acting as the end stage effector cytokine in this cascade.2

Stimulation of host IL6 stimulates protective host responses suchas acute phase response and hypothalamus–pituitary–adrenal(HPA) axis. IL6 stimulates hypothalamic corticotropin releasinghormone, pituitary corticotropin and adrenal steroid hormonesynthesis.3 4 Soluble IL6 receptor (sIL6R) is an agonist to IL6 as IL6upon binding to sIL6R further binds to signal transducing gp130protein activating cells that lack membrane bound IL6R. Thus,sIL6R may function as a powerful enhancer of IL6.5

The hypothesis of the present study was that IL6 and theHPA axis form a link between the disease and fatigue associatedwith it, if low serum dehydroepiandrosterone sulfate (DHEAS)levels, which have been found in SS6 and DHEA treatment hasbeen tried,7 play a role as a stimulus driving the host IL6response, then such a substitution dose should downregulatethe IL6 driving the HPA axis.

Patients with primary SS8 with severe fatigue (general fatigue>14 in Multiple Fatigue Inventory-20 (MFI-20)) and low serumDHEAS (below age-matched and sex-matched normal meanvalues) entered the trial. Half of the patients received 50 mgDHEA orally and the other half recieved placebo for 4 months in ablinded manner followed by 1-month washout and thereafter anew 4 month DHEA/placebo period. Patients gave informedwritten consent and the study was approved by the local EthicsCommittee. Fatigue was measured at baseline using MFI-20 (scoresfrom 4 to 20, 20 corresponding to the highest grade of fatigue)9 andvisual analogue scale (VAS) for global fatigue (100 mm correspond-ing to very tired). Global health was assessed with the Short-Form36 (SF-36) questionnaire (scores from 0 to 100, 0 corresponding tothe worst conceivable self-perceived health).10 Blood samples weredrawn in the morning, IL6 and sIL6R were analysed by ELISA(sensitivities: IL6, 0.7 pg/ml, sIL6R, 1.5 pg/ml).

A total of 33 women and 4 men entered the trial, mean (SD)57.6 (11.1) years old, 5.2 (4.9) years since diagnosis, 12.6 (7.3)years since symptoms debuted and erythrocyte sedimentationrate (ESR) 16.9 (11.8) mm/h.

We found that baseline IL6 was statistically significantlyinversely correlated with general fatigue when patients with IL6below the detectable level of the assay were excluded, butotherwise was not (table 1). Soluble IL6R presented stronginverse correlations with general fatigue, reduced activity,

reduced motivation and total score on MFI-20 and with VASfor global fatigue (table 1). Soluble IL6R was positivelycorrelated with vitality and mental component score in SF-36(table 1). Furthermore, substitution with 50 mg DHEA sig-nificantly decreased sIL6R (fig 1).

IL6 stimulates HPA via IL6 receptors to produce stresshormones counteracting fatigue. The more serum IL6, the lessfatigue. This also explains why the significance between thenegative correlation between serum IL6 and fatigue disappears ifpatients are not able to produce IL6 are included in the analysis:as a result of the lack of serum IL6, these patients cannotstimulate the HPA axis but their fatigue is genuine and does notand cannot correlate with serum IL6 values. Second, sIL6Rsenhance IL6 stimulation and the inverse correlation betweensIL6R and MFI-20 provides evidence of ongoing IL6 to IL6R

Figure 1 The effect of substitution with dehydroepiandrosterone(DHEA) and placebo on soluble interleukin (IL)6 receptor concentration inserum in patients with primary Sjogren syndrome (SS). Mean values andstandard error of the means are displayed (bars).

Table 1 Significant correlations (Spearman rank correlationcoefficients) between Multiple Fatigue Inventory-20 (MFI-20), visualanalogue scale (VAS) for global fatigue and Short-Form 36 (SF-36)questionnaire scores, and interleukin (IL)6 and soluble IL6 receptor(sIL6R) at baseline

IL6 sIL6R

MFI-20:

General fatigue 20.50* (21) 20.42** (37)

Reduced activity 20.38* (37)

Reduced motivation 20.42** (37)

Total score 20.42** (37)

VAS global fatigue 20.47** (37)

SF-36:

Vitality 0.49** (37)

Mental component score 0.34* (35)

Only values of IL6 above 0.7 pg/ml were included. The number of patients in eachcorrelation is shown in parenthesis after the respective correlation coefficients.* = p,0.05, ** = p,0.01.

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efficacy of retreatmentrituximab: extended follow-up, safety and Treatment of primary Sjögren syndrome with

J M Meijer, J Pijpe, A Vissink, C G M Kallenberg and H Bootsma

doi: 10.1136/ard.2008.0926012009 68: 284-285 Ann Rheum Dis 

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