- ACRONYMS
- ACR - American College of Rheumatology
- EULAR - European League Against Rheumatism
- RA - Rheumatoid arthritis
- RCT - Randomized controlled trial
- SLE - Systemic lupus erythematosus
- SS - Sjögren's syndrome
- EPIDEMIOLOGY
- Sjögren's syndrome (SS) affects about 2% of the adult population, and it's estimated that about half of those affected go undiagnosed because of its nonspecific symptoms and coexistence with other autoimmune disorders
- SS can present as an isolated condition (primary SS), but in a majority of the cases (up to 60%), it is diagnosed in the presence of other autoimmune diseases (secondary SS). Depending on the study, up to 25% of patients with RA or SLE have histological evidence of SS. [2]
- RISK FACTORS
- Known risk factors
- Female sex - 9:1 female:male ratio
- Age - more common in women around menopause
- HLA DR haplotypes
- Rheumatoid arthritis - up to 25% of RA patients
- Systemic Lupus erythematosus - up to 25% of SLE patients
- Systemic sclerosis [1,2]
- Possible risk factors
- Viral infections of the glands [1]
- SYMPTOMS
- Dry mouth - 90%
- Dry eyes - 85%
- Dry skin - 55%
- Joint pain - 53%
- Fatigue - 50%
- Parotid gland enlargement - 26%
- Muscle pain - 22%
- Peripheral neuropathy - 22%
- Raynaud's phenomenon - 13%
- Rash - 10% [2,3,10]
- PATHOPHYSIOLOGY
- SS is marked by the development of organ-specific autoantibodies including antibodies to cellular antigens of salivary ducts, the thyroid gland, the gastric mucosa, red blood cells, the pancreas, the prostate, and nerve cells
- Non–organ-specific autoantibodies are found in approximately 60% of patients with SS. These autoantibodies include rheumatoid factors, antinuclear antibodies, and antibodies to the small RNA-protein complexes (Ro/SS-A and La/SS-B).
- Histological findings in SS include focal lymphocytic infiltrates located mainly around the glandular ducts of the salivary and lacrimal glands. Other exocrine glands of the respiratory, gastrointestinal tract, and vagina can be affected.
- Glandular inflammation leads to loss of secretions and symptoms of dryness [2]
- DIAGNOSIS
- Laboratories
- Anti-SS-A antibodies (Anti-Ro) - Anti-SS-A antibodies are autoimmune antibodies to Ro proteins. Ro proteins are RNA complexes that are expressed on the surface of glandular cells that are undergoing necrosis or apoptosis. It is during this process that autoimmunity is thought to occur. [1,6]
- Diagnostic value
- Found in 60 - 70% of patients with SS [3,4]
- Also found in 30 - 40% of patients with Lupus [4,5]
- Anti-SS-B antibodies (Anti-La) - Anti-SS-B antibodies are autoimmune antibodies to La proteins. La proteins are RNA complexes that are expressed on the surface of glandular cells that are undergoing necrosis or apoptosis. It is during this process that autoimmunity is thought to occur. [1,6]
- Diagnostic value
- Found in 40 - 60% of patients with SS [3,4]
- Also found in 10 - 15% of patients with Lupus [4,5]
- Anti-SS-B antibodies are associated with congenital heart block and neonatal lupus
- Rheumatoid Factor (RF) - rheumatoid factors are antibodies to the Fc fragment of IgG antibodies. See rheumatoid factor for more.
- Diagnostic value
- Rheumatoid factors are found in ∼ 60% of patients with primary SS [7]
- Antinuclear Antibodies (ANA) - ANAs are antibodies directed at various cellular components. See antinuclear antibodies for more.
- Diagnostic value
- ANAs are found in ≥ 66% of patients with primary SS [7]
- ACR proposed criteria
- A number of diagnostic criteria for SS have been proposed over the years. None have ever been endorsed by the ACR or EULAR. The criteria presented in the table below are criteria proposed by the ACR in 2012.
| ACR 2012 Proposed Criteria for Diagnosing SS |
|---|
|
|
Criteria 1: Positive serology
|
Criteria 2: Positive salivary gland biopsy
|
Criteria 3: Positive keratoconjunctivitis sicca (dry eyes) test
|
- TREATMENT
- Overview
- Currently, there is no proven therapy that will cure or inhibit the progression of SS. That being said, the treatment of SS is largely symptomatic.
- The ongoing evolution of biological agents offers the best hope for a disease-modifying therapy. To date, no biological therapy has been proven to be effective in a large, randomized controlled trial.
- Dry eyes
- Artificial tears and ointments
- Cyclophosphamide drops (Restasis®)
- Punctal occlusion (blocks tear drainage)
- Goggles or glasses with side chambers [2,8]
- Dry mouth
- Muscarinic agonists - Pilocarpine (Salagen®), cevimeline (Evoxac®)
- Saliva substitutes
- Frequent dental care
- Oral antifungals (e.g. nystatin, clotrimazole) for intraoral candidiasis
- Avoid sucrose
- Systemic symptoms (e.g. joint pain, muscle pain)
- NSAIDs (ibuprofen, naprosyn, etc.)
- Hydroxychloroquine (Plaquenil®) - see studies below
- Methotrexate - for moderate-severe cases
- Corticosteroids - use should be limited to severe disease
- Cyclophosphamide - life-threatening disease
- Biologicals - Tumor necrosis factor inhibitors have not shown a consistent benefit in trials. Rituximab (anti-CD20 agent) may have a possible benefit, but this has not been validated in large trials, and its effects have not been impressive in smaller trials. [2,9,11]
- Other
- Neuropathy - 22% of patients; peripheral sensory neuropathy most common; autonomic neuropathy has been reported
- Kidney disease - common; tubulointerstitial nephritis; glomerulonephritis; proteinuria; renal tubular acidosis
- Sensorineural hearing loss - has been reported in 20 - 40% of patients
- Muscle pain/inflammation - myalgias in 20 - 30% of patients; myositis (muscle inflammation) is common and may be subclinical
- Raynaud's phenomenon - 13% of patients; may indicate systemic sclerosis is present
- Cutaneous vasculitis - up to 10% of patients
- B-cell lymphoma - greatly increased risk; seen in 5 - 10% of patients in some studies
- Lab abnormalities - low blood cell counts - 33%; elevated ESR - 22%; hypergammaglobulinemia - 22%
- Pulmonary disease - bronchial/bronchiolar involvement; usually occurs early in the course of SS; progressive pulmonary disease is rare [2,10]
- STUDIES
- The JOQUER trial enrolled 120 patients with primary SS
Main inclusion criteria
- Meet the American-European Consensus Group Criteria for primary SS
- Receiving stable doses of NSAIDs, corticosteroids, pilocarpine, or topical cyclosporine for at least 4 weeks before enrollment
Main exclusion criteria
- Received rituximab or cyclophosphamide during the 6 previous months or any other immunosuppressant during the previous month
- Recent serious systemic manifestations (e.g. lymphoma, CNS disease, liver disease, kidney disease)
Baseline characteristics
- Average age 56 years
- Female - 91%
- Median time with symptoms - 5 years
- Anti-SSA antibodies - 55%
- Previous systemic involvement - 43%
Randomized treatment groups
- Group 1 (56 patients) - Hydroxychloroquine (HCQ) 400 mg once daily
- Group 2 (64 patients) - Placebo
- Concomitant treatment with a stable dose of nonsteroidal anti-inflammatory drugs, oral corticosteroids, pilocarpine, tear substitutes, and topical cyclosporine were allowed
Primary outcome: Proportion of patients with a 30% or greater reduction between weeks 0 and 24 in scores on 2 of 3 numeric analog scales (from 0 [best] to 10 [worst]) evaluating dryness, pain, and fatigue
Results
| Duration: 24 weeks | |||
| Outcome | HCQ | Placebo | Comparisons |
|---|---|---|---|
| Primary outcome | 17.9% | 17.2% | OR 1.01, 95% CI [0.37 - 2.78], p=0.98 |
|
|||
Findings: Among patients with primary Sjögren syndrome, the use of hydroxychloroquine compared with placebo did not improve symptoms during 24 weeks
of treatment. Further studies are needed to evaluate longer-term outcomes.
- BIBLIOGRAPHY
- 1 - PMID 16039337 Lancet review
- 2 - PMID 15226160 Arch of IM review
- 3 - ACR 2012 criteria
- 4 - LabCorp® website
- 5 - PMID 23993190 - Autoimmune ab review
- 6 - PMID 16178869 - SSA/B
- 7 - PMID 17286756 - Ab in SS
- 8 - Restasis® PI
- 9 - PMID 20664046 - JAMA MA on treatments
- 10 - PMID 15498797 - Annals of rheum review
- 11 - PMID 24727841 - Rituximab trial