566 C.P. Mavragani and S.S. Kassan

Table 38.1 Effect of immunomodulating or immunosuppressive medications in the treatment of primary Sjögren’s syndrome

38.2Antimalarials

Early studies failed to suggest a substantial role of hydroxychloroquine (HCQ) in alleviating sicca symptoms despite this medication’s ability to reduce inflammatory markers within saliva and serum markers of B-cell hyperreactivity, e.g., hypergammaglobulinemia and autoantibody levels [1, 2]. However, recent data from an openlabel, 48-week prospective study of 32 pSS patients suggested that HCQ use led to improvement of subjective symptoms of eye dryness and delayed disease progression. The latter was evidenced by the worsened objective dryness scores (Shirmer’s test, lissamine green, tear break-up time) in the control group 3 months after treatment cessation. Levels of B-cell-activating factor (BAFF) [3, 4] within the tears of patients in the HCQ group were significantly reduced [5]. Another study suggested a potential role of HCQ in improving salivary hypofunction through inhibition of cholinesterase activity within salivary glands [6].

Although its utility in treating sicca symptoms is debatable, HCQ seems to be beneficial for musculoskeletal complaints such as arthralgias, myalgias, fibromyal- gia-like features, and the non-erosive polyarthropathy that is sometimes associated with pSS [1, 2, 7]. Vasculitis has been reported after HCQ cessation in one case [8].

38.3Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Data on the use of NSAIDs in the management of pSS are scarce. These medications can be used with appropriate caution in patients with musculoskeletal complaints.

38.4Glucocorticoids

Although evidence for a beneficial role of glucocorticoids in the alleviation of local symptoms is limited to non-existent [9, 10], these agents play an important role in the management of extraglandular disease manifestations such as interstitial lung disease, glomerulonephritis, autoimmune liver disease, nervous system involvement, and vasculitis. The starting dose of glucocorticoids varies according to clinical judgment and the specific pSS manifestation, but for serious complications generally equates to a daily prednisone dose on the order of 0.5–1 mg/kg of body weight [7, 11, 12]. For CNS involvement, intravenous pulses of methylprednisolone (1 g/day for 3 consecutive days) have been employed but there are no controlled data and no consensus about the appropriate approach to that challenging subset of patients in general. Topical glucocorticoid use in the eyes has been associated with corneal lesions in patients with pSS, and therefore should be employed cautiously [13].

38.5Azathioprine

Given the promising therapeutic results of azathioprine in terms of reduction of the extent of lymphocytic infiltration in NZB/NZW F1 hybrid mice [14], the role of lowdose azathioprine (1 mg/kg body weight/day) was examined in a 6-month, doubleblind, placebo-controlled trial in 25 pSS patients. The authors observed no therapeutic benefit in terms of symptoms, signs, or serologic or histologic markers, but did report a considerable number of reported adverse effects [15]. The authors concluded that azathioprine was unsuitable for the treatment of SS. There may be some patient subsets with particular disease manifestations, however, in which azathioprine use is appropriate. The medication is occasionally used in pSS in patients with interstitial lung disease, glomerulonephritis, and nervous system involvement [7].

38.6Cyclophosphamide

Cyclophosphamide is reserved for serious or life-threatening conditions such as glomerulonephritis refractory to prednisolone, systemic necrotizing vasculitis, or severe neurological involvement. Because of extrapolations from studies of cyclophosphamide in systemic lupus erythematosus, the medication is usually administered intravenously (0.5–1 g/m2 of body surface/month) for a total of 6 months.

appear to modify the natural history of this disorder in most patients, although restricted use for these medications has been advocated, in certain circumstances.

References

1. Tishler M, Yaron I, Shirazi I, et al. Hydroxychloroquine treatment for primary Sjogren’s syndrome: its effect on salivary and serum inflammatory markers. Ann Rheum Dis. 1999;58:253–6.

2. Manoussakis MN, Moutsopoulos HM. Antimalarials in Sjogren’s syndrome – the Greek experience. Lupus. 1996;5 Suppl 1:S28–30.

3. Groom J, Kalled SL, Cutler AH, et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren’s syndrome. J Clin Invest. 2002;109:59–68.

4. Mariette X, Roux S, Zhang J, et al. The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjogren’s syndrome. Ann Rheum Dis. 2003;62:168–71.

5. Yavuz S, Asfuroglu E, Bicakcigil M, et al. Hydroxychloroquine improves dry eye symptoms of patients with primary Sjogren’s syndrome. Rheumatol Int. 2011;31:1045–9. Epub Mar 23, 2010.

6.Dawson LJ, Caulfield VL, Stanbury JB, et al. Hydroxychloroquine therapy in patients with primary Sjogren’s syndrome may improve salivary gland hypofunction by inhibition of glandular cholinesterase. Rheumatology (Oxford). 2005;44:449–55.

7. Mavragani CP, Moutsopoulos NM, Moutsopoulos HM. The management of Sjogren’s syndrome. Nat Clin Pract Rheumatol. 2006;2:252–61.

8. Okan G, Karaaslan M, Büyükbabani N. Systemic vasculitis developing after hydroxychloroquine interruption in a patient with Sjögren’s syndrome. Clin Exp Dermatol. 2010;35:442–3. Epub Nov 3, 2009.

9. Zandbelt MM, van den Hoogen FH, de Wilde PC, et al. Reversibility of histological and immunohistological abnormalities in sublabial salivary gland biopsy specimens following treatment with corticosteroids in Sjogren’s syndrome. Ann Rheum Dis. 2001;60:511–3.

10. Fox PC, Datiles M, Atkinson JC, et al. Prednisone and piroxicam for treatment of primary Sjogren’s syndrome. Clin Exp Rheumatol. 1993;11:149–56.

11. Kaufman I, Schwartz D, Caspi D, et al. Sjogren’s syndrome – not just Sicca: renal involvement in Sjogren’s syndrome. Scand J Rheumatol. 2008;37:213–8.

12. Hawley RJ, Hendricks WT. Treatment of Sjogren syndrome myelopathy with azathioprine and steroids. Arch Neurol. 2002;59:875; author reply 876.

13. Linardaki G, Moutsopoulos HM. The uncertain role of immunosuppressive agents in Sjogren’s syndrome. Cleve Clin J Med. 1997;64:523–6.

14. Yeoman CM, Franklin CD. The treatment of Sjogren’s disease in NZB/NZW F1 hybrid mice with azathioprine: a two-stage study. Clin Exp Rheumatol. 1994;12:49–53.

15. Price EJ, Rigby SP, Clancy U, et al. A double blind placebo controlled trial of azathioprine in the treatment of primary Sjogren’s syndrome. J Rheumatol. 1998;25:896–9.

16. Moutsopoulos HM, Balow JE, Lawley TJ, et al. Immune complex glomerulonephritis in sicca syndrome. Am J Med. 1978;64:955–60.

17. Skopouli FN, Dafni U, Ioannidis JP, et al. Clinical evolution, and morbidity and mortality of primary Sjogren’s syndrome. Semin Arthritis Rheum. 2000;29:296–304.

18.Boumba D, Skopouli FN, Moutsopoulos HM. Cytokine mRNA expression in the labial salivary gland tissues from patients with primary Sjogren’s syndrome. Br J Rheumatol. 1995;34:326–33.

19. Skopouli FN, Jagiello P, Tsifetaki N, et al. Methotrexate in primary Sjogren’s syndrome. Clin Exp Rheumatol. 1996;14:555–8.

20. Skopouli FN, Fox PC, Galanopoulou V, et al. T cell subpopulations in the labial minor salivary gland histopathologic lesion of Sjogren’s syndrome. J Rheumatol. 1991;18:210–4.

21. Drosos AA, Skopouli FN, Costopoulos JS, et al. Cyclosporin A (CyA) in primary Sjogren’s syndrome: a double blind study. Ann Rheum Dis. 1986;45:732–5.

Chapter 39

New Immunosuppressive Agents for the Treatment of Sjögren’s Syndrome

Steven Carsons

Despite the significant success in many immune-mediated disorders of diseasemodifying antirheumatic drugs (DMARDs) such as methotrexate and azathioprine, the demonstration of DMARD efficacy for the control of sicca and extraglandular symptoms of Sjögren’s syndrome (SS) has been elusive. This chapter will discuss potential applications of newer DMARDs for the management of primary SS (pSS) (Table 39.1).

39.1Leflunomide

Leflunomide (LEF) is an oral immunosuppressive agent approved by the US FDA and the European Commission for use in rheumatoid arthritis (RA). Recently, the European Medicines Agency approved LEF for the treatment of psoriatic arthritis

S. Carsons

Division of Rheumatology, Allergy and Immunology, Winthrop-University Hospital,

Mineola, NY, USA

Department of Medicine, Stony Brook University School of Medicine,

Stony Brook, NY, USA

SLE systemic lupus erythematosus, RA rheumatoid arthritis, HBV hepatitis B virus infection, HCV hepatitis C virus infection, HCL hairy cell leukemia, CML chronic myelogenous leukemia, GN glomerulonephritis, IBD inflammatory bowel disease, MS multiple sclerosis

(PsA). LEF, a derivative of isoxazole, rapidly converts to its active form known as A77-1726 in the intestinal mucosa [1]. LEF is a potent inhibitor of orotic acid dehydrogenase which, in turn, results in pyrimidine synthesis inhibition. This preferentially prevents expansion of the lymphocyte ribonucleotide pool and thus, proliferation of activated T lymphocytes. LEF may exert similar action on other immune cells including monocyte/macrophages and B lymphocytes and may inhibit additional enzymes involved in lymphocyte activation and signaling such as tyrosine kinase [2]. Of note, LEF has an exceedingly long half-life (14–18 da.) and is excreted via renal and fecal routes. Blocking enterohepatic recirculation with cholestyramine or charcoal reduces half-life approximately 15-fold and is clinically useful when the drug needs to be rapidly eliminated. LEF is not dialyzable.

Approximately 5% of subjects in RA clinical trials receiving LEF developed liver function test abnormalities. These usually occur during the first 6 months of therapy and resolve in follow-up [3]. Serious LEF-induced hepatotoxicity is thought to be rare [4]. Nevertheless, in 2010, the FDA issued a warning regarding LEF use and the risk of liver injury. Diarrhea occurred in 17% of patients in LEF clinical trials [5], usually within the first 3 months of therapy, and may be associated with the administration of a loading dose. Diarrhea may resolve with continued LEF therapy. A post-marketing survey of greater than 2000 RA LEF-treated patients in Japan identified 29 individuals with interstitial lung disease. Sixty-nine percent had baseline interstitial lung disease prior to initiation of therapy. A review panel determined that the relationship of LEF therapy to the development of interstitial lung disease was probable in 3 and possible in 11 [6]. LEF is teratogenic in rabbits and rats and is contraindicated in pregnancy.

Women and men on LEF who are contemplating conceiving a child should stop LEF and purge existing drug with cholestyramine. Elimination of drug should be documented by serum levels <0.02 mg/L 2 weeks apart. This course should be followed in cases of accidental pregnancy while on LEF.

A pilot study has been published examining the use of LEF for pSS. van Woerkom et al. [7] performed a 24-week, open-label pilot study of LEF (20 mg weekly) on 15 women with pSS. All patients fulfilled the European-American Consensus Criteria and had positive labial salivary gland biopsy (focus score ³ 1). Fourteen of the fifteen patients reached the 24 week endpoint. Twelve attained the 20% overall response endpoint while seven attained the 50% overall response endpoint. Significant improvements from baseline were seen in fatigue scores, serum immunoglobulin concentrations, and rheumatoid factor levels. The Schirmer test improved by 33%. Two patients developed liver function test abnormalities and two became leucopenic. Two patients also developed lupuslike cutaneous lesions de novo and three additional patients had exacerbations of existing lupus-like skin lesions. Antibodies to ds-DNA were not measured as part of this study.

Two additional studies published in abstract form have suggested a role for LEF in pSS. An open-label study in 17 patients who failed glucocorticoid therapy demonstrated an improvement in symptoms and laboratory studies on LEF [8]. A study of laboratory parameters in 18 patients treated with LEF suggested efficacy for SS [9]. Thus, it appears that LEF may be useful in a subset of patients with SS. Additional study is needed to determine the safety in patients with features of cutaneous lupus erythematosus.

39.2Interferon-a

Although the precise etiology of SS is unknown, it is presumed that an environmental trigger stimulates the innate immune system which results in the enhanced elaboration of interferon-a by plasmacytoid dendritic cells. Viral infections are good candidates for this trigger. Despite this, levels of IFN-a have been reported to be depressed in Sjögren’s syndrome. It is hypothesized that therapy with oral IFN may restore salivary gland function. Shiozawa et al. performed a 6-month single-blinded controlled trial involving 56 SS patients who received either 150 IU of IFN or 250 mg of sucralfate orally [10]. This study demonstrated a significant increase in salivary flow by the Saxon test for the IFN group, although only 50% of the IFNtreated individuals responded. Seven of the nine IFN responders who underwent re-biopsy of minor salivary glands showed improvement in the degree of lymphocytic infiltration.

Ship et al. [11] examined the effect of multiple dosages of oral IFN lozenges in a phase II placebo-controlled trial over a 12-week period in 111 patients. Complete response was defined as a 25% improvement in the VAS for oral dryness and a 0.05 g/min increase in unstimulated salivary flow. The percentages of patients who