Implications of long-term medication of oral steroids and antimalarial drugs in primary Sjögren's syndrome

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Abstract

Background

Immunomodulating drugs are commonly used in treating patients with autoimmune diseases but with very different outcomes. We aimed to investigate differences in cytokine and autoantibody levels with regard to patient characteristics in patients with primary Sjögren's syndrome (pSS) receiving oral steroids or antimalarial drugs (AM) after a longer period of time.

Methods

Serum samples from 141 patients fulfilling the revised EU–US criteria and 99 healthy controls were analysed for 25 cytokines and 8 autoantibodies.

Results

AM-patients had lowered levels of IL-5, IL-10, IL-13 and IFN-γ, though non-significantly. Use of prednisolone was associated with reduced levels of IL-15, IL-2, IL-4, IL-12p40, TNF-α, MIP-1α and MIP-1β (p < 0.05), and a trend towards decreased levels of IL-1RA and IL-1β was observed. No associations were seen between AM and antibody levels. Significantly higher protein levels of anti-Ro-52 and anti-Ro-60 were observed in the patients taking prednisolone (p < 0.05). The proportion of patients positive for anti-Ro-52 and anti-La-48 did not differ significantly in the groups taking and not taking prednisolone, but a difference was seen for anti-Ro-60 (p < 0.05).

Conclusions

Prednisolone is a potent anti-inflammatory and immunosuppressive drug commonly used in autoimmune diseases. Our study shows that oral steroids are associated with reduced levels of several pro-inflammatory cytokines, but increased levels of pSS specific autoantibodies. The association between steroid use and increased antibody levels is not readily explained by known steroid effects, and should therefore be confirmed in further studies. Lower levels of pro-inflammatory cytokines indicate a beneficial effect of oral steroids in this patient group.

Highlights

► We find no indications that long-term treatment with oral steroids and antimalarial drugs is harmful. ► Patients treated for up to 10 years do not present with milder symptoms than untreated patients. ► Patients taking oral steroids have higher levels of autoantibodies.

Introduction

Primary Sjögren's syndrome (pSS) is a complex autoimmune rheumatic disease characterised by the presence of autoantibodies against the ribonucleoprotein (RNP) particles Ro/SSA and La/SSB [1], and focal mononuclear cell infiltration of exocrine glands. The salivary and lacrimal glands are the principal targets of a proposed T and/or B cell-mediated chronic inflammation, with an associated glandular atrophy and deficient function. The clinical consequences are dry mouth (xerostomia) and dry eyes (keratoconjuctivitis sicca). Due to disease development in multiple organs, there may be a number of systemic features of SS [2]. Serological markers of inflammation are commonly found in pSS patients, including higher titres of cytokines and circulating antibodies [3], [4]. Several factors may influence cytokine and autoantibody levels, including age [5] and we have previously observed aberrant titres of cytokines with regard to lymphoid organisation in pSS minor salivary glands [6].

The management of patients with pSS is difficult; the aetiology of the disease is largely unknown precluding direct treatment of a specific target. Current therapies include non-pharmacologic measures like punctual occlusion to preserve tears as well as the symptomatic relief of xerostomia and keratoconjuctivitis sicca, and use of immunomodulatory drugs [7], [8]. A range of alternative medications have been tried to prevent tissue destruction [9], provide long-term relief of symptoms [10] and reduce the fatigue often seen in pSS [11]. Anti-TNF-α treatment through Infliximab and Etanercept has been tried in pSS patients though not successfully [[12], [13], [14]], whereas depletion of memory B cells through anti-CD20/Rituximab has been promising in preventing tissue destruction in salivary glands [15]. Hydroxychloroquine and prednisolone have been shown to delay SLE onset [16]. Recent trials of belimumab (anti-BAFF) have shown promising results in phase III studies in SLE patients and might prove useful in pSS in the future (BLISS-study [ClinicalTrials.gov identifier: NCT00410384]).

Immunomodulatory drugs may exert different effects in different diseases, but are in general thought to be of great benefit in autoimmune diseases. In this study, our purpose was to investigate circulating autoantibody and cytokine levels in healthy individuals and pSS patients treated with antimalarial drugs and prednisolone over a longer period of time to see whether levels normalise.

Section snippets

Patients and controls

The pSS cohort comprised patients (n = 141) diagnosed according to the revised European-American criteria [17] at the Department of Rheumatology, Haukeland University Hospital, Bergen, Norway. The cohort contained seven men and 134 women, mean age was 56 years (range: 24–74 years).

Nineteen (13.5%) patients had discontinued the use of prednisolone, eleven (7.8%) still used prednisolone and 111 (78.7%) patients had never used prednisolone. The median dose of prednisolone was 5 mg/day (range: 2–50 

Serum cytokines and autoantibodies

Serum cytokine and autoantibody protein levels were generally elevated in pSS patients compared with the healthy controls, both for growth factors, chemokines and pro- and anti-inflammatory cytokines (Fig. 1A). Of the 99 controls, six had unexpectedly high cytokine levels, indicative of current or recent infection or inflammation.

A two-fold increase was noticed in interleukin (IL) 1β, the IL-12 and IL-23 subunit IL-12p40, macrophage inflammatory protein (MIP) 1β, monokine induced by

Discussion

The effect of anti-inflammatory and immunomodulatory therapy on systemic cytokine and autoantibody levels in pSS has previously been poorly investigated. Though the drugs may be useful in relieving pain and reducing inflammation [18], as well as relieving ocular and oral symptoms [19], the pharmacological effect of antimalarial drugs in rheumatic diseases is not known. We were unable to detect signs of lower rate of autoantibody accumulation as previously reported for systemic lupus

Acknowledgements

This work was financially supported by the Strategic Research Program at Helse Bergen, Western Norway Regional Health Authority, and the Broegelmann Foundation.

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