*7.2. Systemic Manifestations*

Management of visceral manifestations linked to disease systemic activity is currently based only on rare randomized controlled trials, cohort studies or case-reports [334]. Treatment regimens are often borrowed from systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), mixed cryoglobulinemia or idiopathic organ-specific autoimmune disease management.

Therapeutic regimen must be tailored to organ specific involvement and severity of the disorder. This approach requires organ-by-organ examination of disease activity and pre-existing damage. To this end, ESSDAI score may be used as a guide but does not take into count all the systemic manifestations of pSS [210]. As a rule of thumb, systemic immunosuppressive therapy will only be offered to patients with moderate or severe organ activity (as define in ESSDAI score) or moderate overall systemic activity (ESSDAI ≥5) [210]. Organ manifestation classified as mild usually requires only self-care advice, local treatment or pain relief medication (NSAID for inflammatory arthralgia or co-analgesic for neuropathic pain). In case of treatment failure, low-dose corticosteroid treatment and/or conventional DMARD may be considered depending on clinical manifestation.

In cases requiring immunosuppressive therapy, an induction/remission biphasic regimen is recommended for the rapid control of organ damage and the preservation ofits function [210]. Corticosteroid therapy is an almost essential treatment for moderate to severe systemic manifestations. To date, no steroid-free regimen has been studied in pSS and 95% of the published regimens include corticosteroid therapy, alone or in combination with an immunosuppressant [210]. When immunosuppressive therapy is prescribed, itis usually a conventional broad-spectrumimmunosuppressant used as a cortisone-sparing or as a remission-inducing agent: hydroxychloroquine, methotrexate, other conventional DMARDs (leflunomide, salazopirine), mycophenolate mofetil or cyclosporine. As there are no head-to-head comparisons, the choice of immunosuppressant is mainly based on the clinician's experience and on the therapeutic regimens used in idiopathic or lupus-related disorders (HCQ and MTX in skin and articular involvement, AZA, CyA or MMF in pulmonary or renal involvement). Severe life- or organ-threatening manifestations (central nervous system involvement, glomerulonephritis), generally require an aggressive regimen including methylprednisolone pulse-therapy combined with an alkylating agent (usually cyclophosphamide IV or PO, more rarely chlorambucil) as remission-inducing agents. IVIG at immunomodulatory doses are used in neuropathies or myositis. Biological therapies (mainly rituximab) generally come only in the

third line as rescue therapies. The exception to this rule concerns the manifestations associated with cryoglobulinemia where rituximab is proposed as an immunosuppressant of choice, in combination with corticosteroid therapy or even plasmapheresis in life-threatening cases. As with other autoimmune diseases, corticosteroid therapy should be reasoned with a tapering regimen guaranteeing the shortest possible exposure to supraphysiological doses while maintaining remission. Complications of chronic corticosteroid therapy must be addressed proactively.

Hydroxychloroquine is commonly used as first line DMARD for moderate systemic manifestations mainly affecting the skin and joints. Its use is mainly based on the similarities between pSS and SLE, as pSS is sometimes considered as "lupus of mucous membranes". As opposed to SLE, the evidence for its use in systemic manifestations of pSS does not actually exist, and its use is completely empirical. The first—JOQUER trial—attempting to demonstrate the effect of hydroxychloroquine over 24 weeks failed to reach the primary endpoint (30% or greater reduction between weeks 0 and 24 in scores on 2 of 3 VAS (dryness, pain, and fatigue)) [335]. In a more recent RCT performed over 2 weeks, no effect of hydroxychloroquine was seen on BUT test, Schirmer test, corneal staining score or OSDI score [336]. While those RCT have not been designed to investigate the effect of the drug on systemic manifestations of the disease, and the number of patients was small, hypergammaglobulinemia statistically improved significantly [335,336].
