Treatment Options for Sjogren's Syndrome

Systemic Treatments for Severe Sicca Syndrome and Extraglandular Sjogren's Syndrome

With the exception of pilocarpine and cevilemine to treat dry mouth symptoms, there are no medications that have been approved by the U.S. Food and Drug Administration (FDA) for treatment of severe glandular or extraglandular symptoms associated with Sjogren's syndrome. Disease modifying antirheumatic drugs (DMARDs) such as those used for rheumatoid arthritis and systemic lupus erythematosus (SLE) have had limited success in the treatment of severe primary Sjogren's syndrome though they may be effective on a limited basis in managing extraglandular manifestations. Medications to treat Sjogren's syndrome and the systemic manifestations are chosen on the basis of what seems to work for other patients and are modified on an as-needed basis.

In general, medications used for the treatment of severe Sjogren's syndrome and various systemic manifestations of Sjogren's syndrome include:

  • Anti-inflammatory drugs, such as aspirin, Motrin or Advil. Some of these medications may be administered as a topical cream or suppository for patients who have difficulty swallowing pills.

  • Immunosuppressive drugs

    • corticosteroids (e.g., Prednisone). Use of corticosteroids is limited by their side effects, including: osteoporosis, diabetes, mood changes, and cardiovascular changes. In addition, they accelerate the development of periodontal disease and oral candidiasis.
    • methotrexate (Trexall)
    • azathioprine (Imuran) - studies regarding the efficacy of this drug have so far been inconclusive.
    • cyclophosphamide (Cytoxan) - an alkylating agent used to treat many types of cancer. In Sjogren's syndrome, it may be used for potentially life threatening conditions but it is used with caution due to the high risk of lymphoma. To minimize this risk, some clinicians recommend pulse treatment rather than daily administration.
    • cyclosporine

  • Disease Modifying Antirheumatic Drugs (DMARDs)

    • hydroxychloroquine (Plaquenil) - regular eye checkups are recommended when taking this drug since an uncommon side effect is accumulation of this drug in the eye.
    • leflunomide

  • Biological agents (immunomodifying drugs)

    • infliximab (Remicade) - this is a recombinant anti-tumor necrosis factor monoclonal antibody. To date, data regarding the efficacy of infliximab have been inconclusive, with some small studies indicating significant improvement of symptoms while a 2004 multicenter, randomized, double-blind study clearly showed a lack of efficacy. It is not used as a first-line treatment but may be effective for some types of severe, refractory extraglandular features of Sjogren's syndrome.
    • rituximab (Rituxan) - this is an anti-CD20 monoclonal antibody that appears of have an effect on B-cell hyperactivation which is closely associated with Sjogren's syndrome and with development of B-cell lymphoma.
    • interferon-alpha - improved salivary output and decreased lymphocytic infiltration have been reported in some studies.
    • etanercept (Enbrel) - data regarding the efficacy of etanercept is not conclusive.
    • eculizumab (Soliris)

  • Other medications:

    • thalidomide (Thalomid)
    • dehydroepiandrosteron (DHEA)
    • octreotide (Sandostatin)
    • antiviral agents
    • vitamin b12

Biological Agents

Biological agents target specific factors in the autoimmune response, such as B-cells and T-cells, and are a major advance for the treatment of glandular and extraglandular symptoms in patients with Sjogren's syndrome. Anti-B-cell medications have not been approved by the U.S. Food and Drug Administration (FDA) at this time. They are used for patients with severe cases of Sjogren's syndrome who are refractory to standard therapy of corticosteroids and other immunosuppressive agents or patients with a life threatening situation. The overall long-term risk of biological agents is unknown. Rituximab was approved in 1997 to treat B-cell lymphoma. It is also used to treat various autoimmune disorders such as rheumatoid arthritis.

Rituximab is a very promising drug for the treatment of severe Sjogren's syndrome and may have a role in modifying the disease process based on its effective treatment for systemic lupus erythematosus (SLE) which also is characterized by significant B-cell hyperactivity.

Various studies of patients with Sjogren's syndrome who were treated with rituximab showed benefit for:

  • Improvement of sicca syndrome
  • Improvement in salivary gland production
  • Improvement in extraglandular manifestations such as mixed cryoglobulinemia, refractory pulmonary disease, and peripheral neuropathy
  • Severe arthritis
  • B-cell lymphoma - small studies have reported complete remission in some patients with MALT lymphoma.

Adverse effects of rituximab include:

  • Infusion reaction (up to 35% of cases)
  • Neutropenia (abnormally low levels of neutrophils in the blood)
  • Serum sickness (severe reaction due to the introduction of a foreign substance)

Rituximab is typically administered with corticosteroids and not as a monotherapy. In 2006, the FDA issued a warning regarding fatal progressive multifocal leukoencephalopathy in patients with SLE taking rituximab. This serious side effect has not been seen in patients with Sjogren's syndrome but clearly, patients on rituximab should be carefully monitored for the development of any neurological symptoms.

Eprazumab is another B-cell target therapy which was developed to treat non-Hodgkins lymphoma and has shown promising results for treatment with SLE. Small studies involving patients with Sjogren's syndrome are inconclusive but investigation is continuing on this promising medication.

For further information, please click on the following link: http://www.medifocus.com/abstracts.php?gid=RH001&ID=17586555

Management of Musculoskeletal Symptoms

Muscle and joint pain associated with Sjogren's syndrome can usually be effectively treated with:

  • Analgesics such as aspirin or non-steroidal anti-inflammatory drugs (e.g., Motrin, Advil) are the first-line of treatment for musculoskeletal symptoms.

  • Low-dose corticosteroid therapy (e.g., prednisolone) is usually reserved for patients suffering from:

    • severe joint pain or arthritis
    • cutaneous symptoms
    • severe oral and ocular sicca symptoms
    • myositis (inflammation of muscle tissue) and neuritis (nerve inflammation)

  • Hydroxychloroquine (Plaquenil) -Short term studies noted improvement in musculoskeletal symptoms such as arthralgia, myalgia, malaise, or fatigue; as well as in some immune markers such as:

    • ANA - antinuclear antibody
    • rheumatic factor
    • erythrocyte sedimentation rate

Management of Fatigue

Patients with significant fatigue should also be evaluated and treated for other conditions such as:

  • Depression
  • Hypothyroidism
  • Fibromyalgia
  • Lymphoma

Exercise may be beneficial for some Sjogren's syndrome patients suffering from fatigue. Patients should consult their health care provider to determine what an appropriate level of exercise would be. A small study showed an improvement in fatigue after treatment with etanercept but there have not been any large-scale clinical trials which confirmed this finding.

Management of Vasculitis

Management of vasculitis may include:

  • Corticosteroid creams
  • Intravenous cyclophosphamide and high dose corticosteroids
  • Plasma exchange (plasmapheresis) for severe complications of cryoglobulinemia vasculitis
  • Intravenous immunoglobulins (IVIG)
  • Rituximab

Raynaud's phenomenon may be treated with calcium-channel blockers or ACE (angiotensin-converting-enzyme) inhibitors. In addition, patients should try to avoid situations of physical or emotional stress.

Management of Pulmonary Symptoms

Severe pulmonary symptoms are rare in Sjogren's syndrome but, if they do develop, may be treated with corticosteroids. Pneumonia or bronchitis is typically treated with antibiotics. Some clinicians recommend immunization against pneumococcal infection. Use of a humidifier to keep the air moistened may also relieve some symptoms such as a dry, hacking cough.

Management of Renal Symptoms

Renal (kidney) involvement in patients with Sjogren's syndrome is typically subclinical. In severe cases, management may include:

  • Corticosteroid therapy
  • Pulse intravenous cyclophosphamide combined with prednisolone for glomerulonephritis
  • Oral potassium and sodium bicarbonate for acidosis
  • Plasmapheresis (exchange of plasma)

Management of Gastrointestinal and Hepatobilliary Symptoms

  • Gastroesophageal reflux can usually be controlled with medications such as antacids, histamine-2 (H-2) blockers, or proton-pump inhibitors.
  • Sjogren's patients who develop mild hepatitis may require no specific treatment, however, liver function tests should be performed to monitor the course of the hepatitis. Patients with persistently elevated liver function tests may be treated with corticosteroids and azathioprine.
  • Some patients with Sjogren's syndrome develop a condition called primary biliary cirrhosis that can lead to cirrhosis (hardening) of the liver. Treatments for primary biliary cirrhosis may include vitamin and calcium supplementation and other symptomatic treatments. In cases where liver damage is extensive, liver transplantation may be necessary.

Management of Neurological Symptoms

Peripheral and sensory neuropathy typically do not respond well to treatment but they often stabilize over time. Some patients with severe sensory neuropathy reported benefit from infliximab which may indicate that TNF-alpha drugs play a role in patients with other severe extraglandular involvement. Some patients with peripheral or cranial neuropathy and Sjogren's syndrome report benefit from other medications such as:

  • Corticosteroids
  • Pulse intravenous cyclophosphamide combined with corticosteroids
  • Azathioprine and methotrexate (if cyclophosphamide is not effective or not well tolerated)
  • Low-dose antidepressants
  • Anti-inflammatory agents
  • Anticonvulsive agents (e.g., gabapentin)
  • Plasmapheresis

Patients who fail to respond to more conservative measures should be thoroughly evaluated by a neurologist who can determine if there are other treatment options available.

Management of Gynecologic Symptoms

Vaginal lubricants can help make intercourse less painful and more comfortable. Vaginal estrogen creams may also be used to treat vaginal dryness by increasing capillary blood flow to the vaginal and vulvar area. Creams containing vitamin E or vitamin E oil are effective for lubricating the external vulvar surface and for relieving painful intercourse.

Examples of creams that may relieve vaginal dryness include:

  • Replens (polycarbophil)
  • Durex Sensilube

Both of these creams are able to cling to the vaginal surface and rehydrate the surface cells and are effective for up to 72 hours. Cortisone creams should be avoided.

Management of Hematologic Symptoms

Hematologic symptoms associated with Sjogren's syndrome are managed with medications including:

  • Corticosteroids
  • Immunosuppressants
  • Azathioprine
  • Cyclophosphamide
  • Methotrexate
  • Intravenous immunoglobulin (IVIG) combined with corticosteroids
  • Plasmapheresis

Management of Lymphoproliferative Disorder

  • Rituximab is a first line therapy for B-cell lymphomas. Most lymphomas in Sjogren's patients are treated with the same protocols as lymphoma in the general population.
  • Epratuzumab is under investigation for treatment of B-cell lymphoma
  • 2-chloro-2-deoxyadenosine is used for treatment of non-Hodgkin lymphoma (NHL) and is being investigated for treatment of NHL associated with Sjogren's syndrome
  • Interferon-alpha has been associated with decreased lymphocytic infiltration in some small studies
  • Hydroxychloroquine - for lymphadenopathy