Endocrinology Metabolism

Systemic Lupus Erythematosus and Osteoporosis

Systemic Lupus Erythematosus (SLE) and Osteoporosis

SLE is a chronic, inflammatory multisystem disease of uncertain etiology with protean laboratory and clinical manifestations, which primarily affects women. Patients have a variable clinical course and prognosis.

Immunologic dysregulation gives rise to excessive amounts of autoantibodies which result in immune inflammation and/or cytotoxic damage. The clinical features can vary from constitutional symptoms to those that result from inflammation in various organs: skin, mucous membranes, kidneys, joints, lung, heart, gastrointestinal tract, serous membranes, and occasionally, the brain.

Involvement of vital organs, particularly the kidneys and central nervous system, accounts for significant morbidity and mortality.

Classification Criteria for the Diagnosis of Systemic Lupus Erythematosus (SLE) from the American College of Rheumatology (2005) are:

  • Malar rash: Fixed erythema, flat or raised, over the malar eminences

  • Discoid rash: Erythematous circular raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur

  • Photosensitivity: Exposure to ultraviolet light causes rash

  • Oral ulcers: Includes oral and nasopharyngeal ulcers, observed by physician

  • Arthritis: Non-erosive arthritis of two or more peripheral joints, with tenderness, swelling, or effusion

  • Serositis: Pleuritis or pericarditis documented by ECG or rub or evidence of effusion

  • Renal disorder: Proteinuria >0.5 g/d or 3+, or cellular casts

  • Neurologic disorder: Seizures or psychosis without other causes

  • Hematologic disorder: Hemolytic anemia or leukopenia (<4000/L) or lymphopenia (<1500/L) or thrombocytopenia (<100,000/L) in the absence of offending drugs.

  • Immunologic disorder: Anti-dsDNA, anti-Sm, and/or anti-phospholipid

  • antinuclear antibodies: An abnormal titer of ANA by immunofluorescence or an equivalent assay at any point in time in the absence of drugs known to induce ANAs

Any combination of 4 or more of 11 criteria, well-documented at any time during a patient's history, makes it likely that the patient has SLE (specificity and sensitivity are 95% and 75%, respectively).

What Else Could the Patient Have?

The list of possible differential diagnoses is broad. The non-specific clinical features of widespread pain and fatigue mean that in some cases fibromyalgia and other chronic pain syndromes may be appropriate differentials. Indeed, it is important to note that fibromyalgia and chronic pain syndromes and SLE can co-exist in the same patient.

A number of patients will present with a cluster of features suggestive of an autoimmune rheumatic disease, though at initial presentation the final diagnosis appears unclear. A proportion of these "undifferentiated" patients will go on to develop full blown SLE, or other diseases such as systemic sclerosis, rheumatoid arthritis, or vasculitis.

Some malignancies, particularly lymphoma and leukemia can present with a similar clinical picture. Similarly, there is significant overlap with the presentation of some infections, notably, tuberculosis, HIV/AIDS and bacterial endocarditis. In view of the immunosuppressive nature of the required drugs, it is clearly crucial to exclude underlying infection before starting treatment for SLE.

Key Laboratory and Imaging Tests

Positive anti-nuclear antibodies (ANA) are found in over 90% of patients with SLE. Significant titers are accepted to be of 1:80 or greater. ANA although sensitive, is far from specific for SLE. A positive ANA is also seen in many other illnesses including systemic sclerosis, polymyositis, rheumatoid arthritis, as well as some chronic infections. All patients should be screened for extractable nuclear antigens (ENA). Different ENAs are associated with different disease manifestations – for instance, anti-Sm is associated with renal involvement, and anti-Ro with secondary Sjogren's syndrome.

Antibodies to double-stranded DNA (dsDNA), and more recently to nucleosomes (though this test is not commonly available in most routine labs) are more specific for SLE, and anti-dsDNA titers are also predictive of renal involvement. The titers of these antibodies fluctuate with disease activity and therefore serial testing is a useful monitoring tool. Disease flares are often accompanied by a rising titer of dsDNA antibodies and erythrocyte sedimentation rate (ESR), and falling complement and lymphocyte count. The C-reactive protein (CRP), unlike the ESR, does not usually rise with disease activity unless there is arthritis or serositis, and a raised CRP in a patient with SLE must always make you consider infection.

Other Tests That May Prove Helpful Diagnostically

Organ involvement, whether it is skin, kidney, lung, heart, or even brain may require pathological confirment by biopsy with immunofluorescence stains.

Management and Treatment of the Disease

SLE is a relapsing and remitting disease, and treatment aims are threefold: controlling day to day symptoms, managing acute periods of potentially life-threatening manifestations, and minimizing the risk of flares during periods of relative stability.

At the milder end of the spectrum, hydroxychloroquine is commonly used. This is effective for skin disease, joint pain and fatigue. Non-steroidal anti-inflammatory drugs are also useful for arthralgia and arthritis, though more aggressive treatment with methotrexate may be required. Low dose oral steroids are often used for mild disease, but immunosuppressive therapies and high dose steroids are generally reserved for major organ involvement.

The most common SLE manifestation requiring high dose and long term corticosteroid therapy is lupus nephritis. Therapy differs depending on the renal pathologic lesion. It is important to treat extra renal manifestations and other variables that may affect the kidneys.

Immunosuppressive agents, particularly cyclophosphamide, azathioprine, or mycophenolate mofetil are used if the patient has aggressive proliferative renal lesions, as they improve the renal outcome. They can also be used if the patient has an inadequate response or excessive sensitivity to corticosteroids

In an attempt to improve management, biological therapies are being used which target specific cells or molecules within the abnormally functioning immune system. For example, the depletion of B cells using rituximab, an anti-CD20 monoclonal antibody previously used in the treatment of B cell lymphomas, is now being used in patients with severe disease which has not responded to conventional treatments.

The latest biological agent, Belimumab (trade name Benlysta) is a fully human monoclonal antibody that inhibits B-lymphocyte stimulator (BLyS), also known as B cell activation factor of Tumor Necrosis Factor family (BAFF) and has been approved for the treatment of SLE. Belimumab has been shown to significantly decrease corticosteroid requirements in SLE patients; it has not been studied in lupus nephritis.

The risk of bone loss in SLE patients is high, especially because lupus patients are being treated more effectively and therefore have increased life span.

Several studies have reported that SLE patients have lower lumbar spine bone mass than controls of similar ages. SLE patients also have a higher risk of vertebral fractures than controls. Of significance is that most of these fractures occur in premenopausal women.

The causes of bone loss are multifactorial. Bone loss is apparent early in the disease, most likely due to cytokines that promote osteoclast function (tumor necrosis factor, interleukin 1, interleukin 6). Proinflammatory cytokines produced in inflamed joints promote the generation and release from the bone marrow of osteoclast precursors (OCPs). Corticosteroids add to bone loss at all stages of SLE. Bone turnover becomes uncoupled, with significantly more osteoclast-mediated bone resorption than bone formation. It is theorized that during acute and chronic inflammation activated T cells and synovial-like fibroblasts can stimulate osteoclastogenesis through the production of RANKL and TNF. TNF can stimulate maturation of osteoclasts and osteoblasts to release RANK Ligand and the, maturation, activity, and survival through induction of RANKL by bone lining cells.

The traditional risk factors for osteoporosis are also seen in SLE patients: age, weight, Asian or Caucasian ethnicity, peak bone mass, history of fracture, family history of fracture, excessive alcohol and cigarette smoking.

There are also metabolic conditions more commonly seen in SLE that increase the risk of bone loss: vitamin D deficiency from dietary causes, sun avoidance, and/or obesity, thyroid disease and possibly, hyperhomocysteinemia. Cyclophosphamide and gonadotropin-releasing hormone agonists are also thought to reduce bone density by changing estrogen and follicle-stimulating hormone levels.

Bone mineral density testing should be done in all SLE patients at risk for osteoporosis, especially those starting corticosteroids and/or cyclophosphamide, and in postmenopausal women. Calcium and vitamin D supplementation provides general prophylaxis. If homocysteine levels are high, folic acid should be given at 1mg per day. Hormone replacement should be used in hypogonadal women unless contraindicated by the disease itself (given the cardiovascular and thromboembolic risks in SLE patients).

In subjects at high risk for fracture, particularly postmenopausal women, bisphosphonate therapy should be considered. If bisphosphonate therapy is considered for premenopausal women a discussion must be had with patients in terms of unknown risk to a fetus given the long skeletal half-life of these medications and that these drugs cross the placenta.

What’s the Evidence?/References

Lane, N. "Therapy Insight Osteoporosis and Osteonecrosis in Systemic Lupus Erythematosus". Nature Clin Pract Rheum. vol. 20. 2006. pp. 562-9.

(A review of potential mechanism of osteonecrosis in SLE patients.)

Bultink, IEM. "Prevalence of and risk factors for low bone density and vertebral fracture in patients with systemic lupus erythematosus". Arthritis Rheum. vol. 54. 1999. pp. 2044-50.

(A review of identifiable risk factors for bone loss particular to SLE.)

Kipen, Y. "Prevalence of reduced bone mineral density in systemic lupus erythematosus and the role of steroids". J Rheumatol. vol. 24. 1997. pp. 1922-9.

(This article highlights the reduced BMD in patients with SLE compared with matched healthy controls and that premenopausal women taking corticosteroids are especially affected.)

Petri, M. "Review of classification criteria for systemic lupus erythematosus". Rheum Dis Clin North Am. vol. 31. 2005;May. pp. 245-54.

(The Systemic Lupus International Collaborating Clinics, in preparation for revising the ACR classification criteria for systemic lupus erythematosus, reviewed the current classification criteria. This paper reviews and critiques previous classification attempts.)

Navarra, SV. "Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial". Lancet. vol. 377. 2011. pp. 721-31.

(The efficacy and safety of the fully human monoclonal antibody belimumab (BLyS-specific inhibitor) is assessed in patients with active systemic lupus erythematosus.)
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