Self Under Siege

The Diagnosis & Management of Autoimmune Disease

By Melissa A. Cunningham, M.D., Ph.D., Paula S. Ramos, Ph.D., Eric S. Zollars, M.D., Ph.D., and Kimberly McGhee

Upon completion of this article, readers should be able to:

• Recognize that systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are appropriately diagnosed based on clinical signs and symptoms together with laboratory findings, but not on the basis of laboratory findings alone.
• Summarize why corticosteroid therapy is not advised long-term in SLE patients and should be avoided if possible in SSc patients.
• Explain the importance of early diagnosis/intervention and routine screening for cardiopulmonary and renal disease in SSc patients.

Autoimmune diseases (ADs) are a family of more than 80 chronic, and often disabling, illnesses characterized by dysfunction of the immune system, activation of autoreactive lymphocytes, and development of immune responses to many self-antigens. The increased levels of autoantibodies can lead to chronic inflammation and organ damage. Patients often endure lifelong debilitating symptoms.

Most ADs exhibit sex and ethnic disparities. Nine out of ten people with systemic lupus erythematosus (SLE) are women, and people of African, Asian, and Native American ancestry are at higher risk for the disease than those of European descent. Those of African ancestry are also at greater risk for systemic sclerosis (SSc, scleroderma) and often develop SLE and SSc earlier in life and experience more severe disease than those of European descent.¹

Sex Bias in Autoimmune Disease

Why are some ADs and female sex so closely entwined Sex chromosomes and sex hormones are each thought to play a role.² The role of the X chromosome in SLE is supported by evidence showing that men with Klinefelter syndrome, who have at least one additional X chromosome (XXY), are much (14- to 18-fold) more likely to develop SLE than controls.^3,4 But the etiology of SLE cannot be explained by a surfeit of X chromosome alone. Women of child-bearing age (ages 15-45) are nine times more likely than men to develop SLE, whereas premenopausal or postmenopausal women are only three times as likely to develop the disease, pointing to a role for sex hormones, especially estrogen.² SLE patients have higher serum levels of estrogen metabolites, suggesting dysfunctional estrogen metabolism, and lower levels of androgens. Administering estrogen to lupus-prone male or female mice worsens disease, whereas administering androgen slows disease progression.⁵

Although less likely to develop the disease, men and children with SLE are more likely to develop severe disease with organ damage and central nervous system involvement. “Estrogen receptor variants, estrogen, and other hormones may play a role in disease pathogenesis, but they may also be protective to some degree once you have the disease,” says MUSC Health rheumatologist and SLE investigator Melissa A. Cunningham, M.D., Ph.D.

Genetic Etiology of Autoimmune Disease

Multiple lines of evidence suggest some degree of common genetic etiology in ADs, including clustering of multiple ADs in families and in individuals, and the number of confirmed genetic regions predisposing to several ADs. This genetic overlap is exemplified by the well-known associations of the Human Leukocyte Antigen (HLA) region with all ADs, as well as other loci associated with multiple ADs, such as IL23R, TNFAIP3, and IL2RA.⁶ A recent review summarizes the ADs with published genome-wide association studies (GWAS) and the number of disease-associated loci uncovered from these GWAS.⁷ It is the general consensus that there is a common genetic background predisposing to autoimmunity, and that further combinations of more disease-specific variations at HLA and non-HLA genes, in interaction with epigenetic (e.g., DNA methylation, histone modifications, non-coding RNA), and environmental factors, contribute to disease, and its clinical manifestations.

Systemic Lupus Erythematosus

SLE is a chronic AD that can damage any part of the body, including the skin, joints, and organs. Repeated flares and remissions are common, with organ damage accumulating with each flare. About 80 percent of SLE patients develop arthritis, and 60 percent develop renal disease. In many SLE patients, autoantibodies attack the hematologic system, leading to thrombocytopenia, leukopenia, and anemia.

Screening & Diagnosis

It is vital that patients with suspected SLE who show signs of organ involvement be seen promptly by a rheumatologist; however, wait times for appointments can be long because of referrals based mainly on laboratory testing and generalized complaints of pain. A recent retrospective study showed that 90 percent of patients referred for a rheumatology consult based largely on a positive antinuclear antibody (ANA) test did not have an ANA-associated AD. The poor predictive value of ANA testing observed in this study was attributed to the fact that most tested patients had a low pre-test probability for ANA-associated rheumatic disease.⁸

Joint pain is indeed a symptom of SLE, but it is also associated with many other diagnoses, including osteoarthritis and rheumatoid arthritis. SLE most commonly occurs in women of child-bearing age (15-45 years), especially women of African, Asian, or Native American ancestry, and thus clinical suspicion for SLE should be much lower in a 65-year-old woman with knee pain than, for example, a 25-year-old African American woman who is complaining of joint pain and may also have other associated SLE symptoms. The constellation of SLE symptoms include Raynaud’s phenomenon, in which digital vasospasms impede blood flow, causing color changes to the skin (white/hypoxic, blue/cyanotic, and red/reperfused), extreme fatigue, alopecia, photosensitive malar/butterfly rashes on the nose and cheeks or discoid rashes, pleurisy or pericarditis, and evidence of organ damage, such as proteinuria, which is suggestive of renal involvement.

ANA testing should be ordered in a clinical context that is suggestive of AD. Positive results do not confirm an SLE diagnosis, as up to 15 percent to 20 percent of people can have a positive ANA without associated disease. Over-ordering ANA testing and referring based on those tests alone, without a strong clinical rationale, results in undue stress for patients who endure weeks to months of worry until the diagnosis is excluded by a rheumatologist. Better notation of clinical symptoms suggestive of SLE can help specialists better triage patients.

Management

Before the antimalarial hydroxychloroquine (Plaquenil®) became the accepted first-line treatment for SLE, physicians often relied on corticosteroids to control the inflammation associated with the disease. The anti-inflammatory effects of corticosteroids are seen quickly, whereas several months of hydroxychloroquine therapy may be necessary before a similar benefit is seen. However, hydroxychloroquine has few side effects, lowers cholesterol, and prolongs survival. Its long-term use is associated with a risk of retinal toxicity, making annual eye examinations mandatory. In contrast, long-term corticosteroid use can cause as many or more serious adverse effects than SLE itself, including osteoporosis, cataracts, hypertension, diabetes, metabolic syndrome, and avascular necrosis. Higher doses of corticosteroids are implicated in organ damage.

Physicians today should not rely on long-term corticosteroid treatment for SLE patients.⁹ Hydroxychloroquine should be begun in all SLE patients, if there is no contraindication, and corticosteroids should be used only to control acute flares and for the shortest time possible at the lowest effective dosage.⁹

Other drugs used to treat SLE are immunosuppressants often prescribed for rheumatoid arthritis, such as methotrexate (Rheumatrex™), mycophenolate mofetil (CellCept®),and azathioprine (Imuran®). These medications help calm the overactive immune systems of SLE patients but can also leave them more vulnerable to infection. The only medication approved by the FDA specifically for SLE is the monoclonal antibody belimumab (Benlysta®), which has proven effective in a subset of SLE patients.

Treating to specified targets in SLE, as has been done in rheumatoid arthritis, is a topic of growing discussion. The T2T (Treat to Target)/SLE recommendations include early identification of lupus nephritis, targeting remission or the lowest disease activity possible to avoid long-term accrual of damage, reducing exposure to corticosteroids, and improving quality of life in SLE patients.¹⁰

Investigational Therapies

MUSC is planning for the first U.S. trial of mesenchymal stem cells derived from umbilical cords as a treatment for refractory SLE (MscISLE; NCT02633163). Mesenchymal stem cells are stromal cells with substantial immunosuppressive properties that are not only pluripotent—capable, for example, of differentiating into bone, cartilage, muscle, marrow stroma, tendon-ligament, fat, and other connective tissues—but are thought to play a role in tissue regeneration and wound repair.¹¹ They have been shown to decrease SLE disease activity without serious side effects in uncontrolled trials in China.¹²

The planned multi-site, phase 2 trial led by MUSC Health rheumatologists Gary S. Gilkeson, M.D., and Diane L. Kamen, M.D.,MSCR, will evaluate whether similar efficacy is shown in a placebo-controlled trial. Cells harvested from umbilical cords will be expanded in MUSC’s Good Manufacturing Practice Quality Clean Cell Facility and infused into patients at MUSC or other study sites. The trial is planned to open in late spring or early summer 2016. For more information, contact Eden Gebre at gebre@musc.edu.

Systemic Sclerosis

SSc is a multisystem fibrosing disease that can involve the skin, heart, lungs, kidneys, and gastrointestinal tract, among other systems. Lung complications, particularly interstitial lung disease (ILD) and pulmonary hypertension, are associated with high morbidity and mortality.

Diagnosis

Quality of life can be improved and organ damage minimized if interventions begin early, before irreparable damage occurs. Early symptoms are subtle and can be missed, delaying referral to a rheumatologist.¹³ The most characteristic symptom of SSc is hardening and tightening of the skin, but not all patients manifest this symptom, and in those who do, the symptom often manifests when much internal organ damage has already been done. The most important harbinger of SSc is Raynaud’s phenomenon, and patients with this condition, especially those with other early symptoms of SSc, including shortness of breath, extreme fatigue, or heartburn, and those with abnormal laboratory findings, should be referred to a rheumatologist.

Management

Corticosteroids, especially in higher doses, should be avoided if at all possible in SSc patients because they can precipitate acute renal crisis. Acute renal crisis, which is characterized by a sudden spike in blood pressure and rapid damage to the kidney, was the number one killer of these patients until the introduction of routine screening and treatment with angiotensin-converting enzyme (ACE) inhibitors.

It is important to recognize that blood pressures still in the normal range (Less than 140/90 mm Hg) that are substantially higher than the patient’s baseline blood pressure may be a signal of impending or ongoing renal crisis. Routine monitoring of blood pressure, prompt treatment with ACE inhibitors if a problem is found, and the avoidance of high doses of corticosteroids in these patients should ensure that gains against this killer are solidified. Due to the high risk of pulmonary hypertension and ILD in SSc, annual monitoring with echocardiography and pulmonary function tests is required.

Although there is no cure for SSc, early referral of patients to specialists to better manage their disease and prevent or minimize organ involvement can improve survival and quality of life. Patients under specialty care are also more likely to be enrolled in clinical trials.

Investigational therapies

Interest in drug therapy for SSc, which is considered a prototype of fibrosing disease, has never been greater. It has been estimated that 45 percent of all deaths in developed countries result from fibrosis (e.g., heart, lung, liver), and the pharmaceutical industry is very interested in developing drugs for SSc that could also be applied to more prevalent fibrosing diseases. Investigators in the Division of Rheumatology at MUSC are on the forefront of drug development for SSc. Carol A. Feghali-Bostwick, Ph.D., received a Small Business Technology Transfer grant from the National Institutes of Health to partner with a biotech company to develop a drug from an anti-fibrotic molecule that she discovered. The laboratories of Elena V. Tourkina, Ph.D., Stanley R. Hoffman, Ph.D., Galina S. Bogatkevich, M.D., Ph.D., and Richard M. Silver, M.D., are developing additional anti-fibrotic molecules.

MUSC investigators are also evaluating whether existing drugs could be repurposed to treat SSc. With funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Dr. Silver is investigating the safety of dabigatran (Pradaxa®), a thrombin inhibitor that is FDA-approved for atrial fibrillation, and plans to start a clinical trial of this agent in the first quarter of 2016. Industry-sponsored clinical trials evaluating whether two existing drugs (Riociguat® and Abatacept®) are effective in SSc are currently recruiting patients. For more information about clinical trials in SSc, contact Kelley Kajdasz at gibsonke@musc.edu or Dana Rosson at rosson@musc.edu.

References

¹ National Institutes of Health. (2005). Progress in Autoimmune Diseases Research. In National Institute of Health Publication No 05-514.

² Moulton VR, Tsokos GC. Clin Immunol. 2012 Jul;144(1):53-56.

³ Scofield RH, et al. Arthritis Rheum. 2008 Aug;58(8):2511-7.

⁴ Seminog OO, et al. Autoimmunity. 2015 Mar;48(2):125-128.

⁵ Lahita RG. Curr. Opin. Rheumatol. 11 (1999) 352-356.

⁶ Ramos PS, et al. PLoS Genet 2011; 7:e1002406.

⁷ Ramos PS, et al. J Hum Genet. 2015 Nov;60(11):657-64.

⁸ Abeles AM, Abeles M. Am J Med. 2013 Apr;126(4):342-8.

⁹ Jordan N and D’Cruz D. Ther Adv Musculoskel Dis 2015, Vol. 7(6) 234–246.

¹⁰ Van Vollenhoven R, et al. Ann Rheum Dis 2014; 73:958-967.

¹¹ Caplan AI. J Pathol. 2009 Jan;217(2):318-24.

¹² Wang D, et al. Cell Transplant. 2013;22(12):2267-77.

¹³ Saketkoo LA, et al. Am J Med Sci. 2014 Jan;347(1):54-63.