September/October 2024

September/October 2024 Issue

Lupus in Older Adults
By Mark D. Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 17 No. 5 P. 18

Awareness of the characteristics of late-onset lupus can help clinicians intervene early to improve outcomes for older adults with the disease.

Systemic lupus erythematosus (SLE), or lupus, is a chronic inflammatory autoimmune disease that can affect any organ or tissue. The Lupus Foundation of America estimates that 1.5 million Americans live with lupus, with 16,000 new cases reported annually.1 The disease can affect people of all ages and genders. Those who experience late-onset SLE, diagnosed after age 50, often have milder symptoms but a higher risk of damage accumulation and lower survival rates compared with those with early-onset SLE. Diagnosis and treatment delays are common, leading to increased disease progression and reduced quality of life. It’s essential for health care professionals to be vigilant in considering the possibility of lupus in older adults, as this can lead to early diagnosis and treatment, significantly improving the quality of life and overall health outcomes in older adults with late-onset SLE.

Types of Lupus
SLE is the most common type of lupus, accounting for 70% of cases.2 It’s the form most people refer to when discussing lupus. SLE can affect almost any organ in the body, including the skin, joints, and kidneys. In contrast, cutaneous lupus affects only the skin and accounts for 10% of cases.2 Another type, drug-induced lupus, also accounts for about 10% of cases and occurs as a reaction to high doses of certain medications such as procainamide and hydralazine.2 Drug-induced lupus symptoms closely resemble those of SLE, but in this case, they typically subside within a few weeks following the discontinuation of the medication.

Who Is at Risk of Developing Lupus?
By increasing their awareness of patients at greatest risk of lupus, health care professionals can help reduce the time to diagnosis and improve treatment outcomes.

Sex and Age
Women, particularly those of childbearing age, are predominantly affected by lupus, comprising 90% of the patient population.2 Although men are less likely to develop lupus, they still account for 10% of lupus cases and tend to have more severe complications, including significant renal impairment, central nervous system, and vascular diseases.2,3 Males also tend to develop lupus at a later age than women.

While the onset of lupus is more common in younger adults, late-onset lupus is reported to occur in up to 25% of all patients.4,5 Across all age groups, women are about 10 times more likely to develop lupus; in late-onset disease, the number of men increases, with women having about a four times greater chance of being diagnosed with lupus than a man of the same age.4 Additionally, the incidence of the disease peaks in women between the ages of 30 and 50, while for men, the peak occurs later between the ages of 50 and 80.6

Race/Ethnicity
Lupus disproportionately affects certain racial and ethnic groups, with Black, Hispanic/Latina, Asian American, Native American, Alaska Native, Native Hawaiian, and other Pacific Islander women experiencing higher prevalence rates.1 The condition can lead to significant health inequalities, with marginalized communities frequently experiencing more aggressive disease and severe complications. For instance, Black patients with lupus are more likely to have organ system involvement, more active disease, and lower levels of social support compared with white patients.7 Further, women from racial and ethnic minority groups tend to develop lupus at a younger age, experience more severe complications, and have higher mortality rates.8 However, it’s crucial for health care providers to recognize that white patients have a higher propensity for developing late-onset lupus compared with those who are Black and Hispanic.4

Etiology
It’s believed that a combination of genetic predisposition and environmental and hormonal factors plays a significant role in the development of lupus.

Genetics
More than 50 genes that are more common in people with lupus have been identified.9 These genes increase susceptibility to environmental factors and raise the odds of developing lupus-associated autoimmunity.10,11

Environmental Factors
Environmental factors implicated in triggering the onset of lupus and worsening flares include ultraviolet light, inhaled exposures (eg, smoking, silica dust, air pollution), gut microbiota dysbiosis, exogenous hormones (eg, oral contraceptives, hormone replacement therapy), lifestyle factors (eg, diet, insufficient sleep, alcohol), viral infections (eg, Epstein-Barr, SARS-CoV-2), chemical exposure (eg, pesticides, mercury), stress and life traumas, and drugs (eg, procainamide, hydralazine, isoniazid, minocycline, tumor necrosis factor inhibitors).10-12

Hormones
Sex hormones, such as estrogen and testosterone, are involved in regulating the immune system and inflammation.13 Higher levels of estrogen may explain the increased prevalence of SLE in females during reproductive years and increased symptoms before menstrual cycles and during pregnancy.14 Conversely, testosterone is an immunosuppressant and reduces proinflammatory cytokines.15 Its protective effects may contribute to a lower prevalence of lupus in males. Studies show that men and women with SLE may have reduced levels of androgens, including testosterone, with low androgen levels linked to a higher prevalence of lupus-associated central nervous system disease and serositis.15

Pathophysiology
Lupus causes immune system dysregulation, autoantibody production, and immune complex formation in organs, leading to complement activation, cytokine release, and widespread inflammation. Subsequent inflammation damages organs and tissues, especially in the joints, skin, brain, lungs, kidneys, and blood vessels.

Symptoms
Lupus is a “great imitator,” causing symptoms that mimic other illnesses, such as chronic fatigue syndrome and fibromyalgia, as well as other autoimmune conditions like rheumatoid arthritis. The symptoms of lupus differ widely from person to person, and its progression is unpredictable. Some patients have sudden increases in symptoms and disease activity, known as flares, while others experience periods of relief, where symptoms lessen or temporarily disappear. This unpredictability requires health care professionals to individualize treatment strategies to meet the unique needs of each patient. Lupus symptoms can affect the entire body, causing fatigue and fever, or be specific to the effects of inflammation on one or more organs. Symptom severity can vary from mild—confined to the skin and joints—to severe manifestations involving life-threatening complications in major organs.

Common symptoms include the following:16

• profound fatigue;
• unexplained fever;
• painful joints and muscles;
• a butterfly-shaped rash across cheek and nose (malar rash);
• anemia;
• swelling in the hands or feet or around the eyes;
• chest pain, especially during deep breathing (pleurisy);
• photosensitivity;
• hair loss (alopecia);
• abnormal blood clotting;
• fingers turning blue or white when cold (Raynaud’s phenomenon);
• ulcers in the mouth or nose;
• headaches; and
• memory problems (brain fog).17

Late-Onset SLE Symptoms and Manifestations
Although individuals with late-onset SLE have varied presentations, some symptoms occur more commonly in them compared with those with early-onset SLE.

Unlike younger patients, who typically develop SLE over a short time, older patients have a more gradual presentation, sometimes taking place over years. Late-onset SLE patients also tend to present with different symptoms than those of younger patients. Compared with early-onset SLE, the initial symptoms of late-onset SLE symptoms are often nonspecific and include fatigue, weakness, joint pain, weight loss, joint pain, muscle aches, fever, brain fog, or mood changes.2

Over time, more specific clinical manifestations develop, with late-onset SLE patients having increased frequency of arthritis; sicca symptoms; pulmonary involvement including interstitial lung disease, serositis, and pleuritis; cognitive dysfunction; and Sjogren’s syndrome—characterized by a cluster of symptoms including dry eyes, dry mouth, dryness of other organs, and fatigue.2 Moreover, some studies report an increased frequency of neurological symptoms such as headaches, neurocognitive dysfunction, and peripheral neuropathy.2 Late-onset SLE patients are also more likely to present with major depression, thrombotic events, cardiac involvement, positive lupus anticoagulant values, and a higher mortality rate.18

In comparison, patients with early-onset lupus are more likely to have a malar rash, photosensitivity, alopecia, Raynaud phenomenon, neuropsychiatric symptoms (seizures and psychosis), and renal involvement.2

Is Late-Onset Lupus More Benign?
Late-onset SLE is often described as having a milder disease course compared with early-onset SLE. However, a study comparing the course of SLE in 1,528 persons, 10.5% of whom were late-onset, found that late-onset SLE involves greater disease activity and comorbidities than early-onset SLE.19 The study’s researchers also summarized important differences seen between the two groups. The early-onset group was diagnosed about two years earlier, had a lengthier illness, and fulfilled more criteria for SLE. The early-onset group also had higher incidences of positive anti-Smith autoantibody, ribonucleoprotein, hypocomplementemia, nephritis, malar rash, cytopenia, and more severe renal disease. However, the older group had a higher comorbidity index with more congestive heart failure and peptic ulcer disease. Also, the older group had higher mean SLE activity, and disease-induced damage was more significant; lupus flares, fatigue, sun rash, dyspnea, paresthesia, and muscle weakness were also more common.

Diagnosis
There is no single blood test, imaging test, or clinical presentation that can definitively diagnose SLE. Diagnosis requires a thorough examination of the patient’s medical history and symptoms, and a combination of various tests is necessary before a diagnosis can be established.

Delayed Diagnosis
The diagnosis of late-onset SLE is often delayed. Lalani et al reported that, on average, for those diagnosed before age 50, it took 2.82 years from the patient’s first lupus symptom to being diagnosed with lupus and 4.83 years for those who were diagnosed after the age of 50.19 Delays in diagnosis in late-onset lupus may be related to a more insidious onset and fewer classic SLE manifestations, misdiagnosis, and lack of physician familiarity with lupus in older adults. Regardless, the consequences of delays in diagnosis are extensive and can lead to increased disease activity, higher levels of damage, fatigue, a lower quality of life, and increased mortality.20

Diagnostic Criteria
Over the years, several classification criteria have been developed to assist with SLE diagnosis. The most recent classification guidelines were developed jointly by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR).21 The 2019 EULAR/ACR criteria require a positive antinuclear antibody for a diagnosis of SLE. If a positive antinuclear antibody is present or has ever been documented, additional criteria from seven clinical and three immunologic domains are used to diagnose SLE. Each domain has criteria assigned a different weight, and a diagnosis of SLE requires a total score of 10 or more.

Clinical domains and criteria include the following:

• constitutional: fever (unexplained);

• hematologic: leukopenia (low white blood cell count), thrombocytopenia (low platelets), autoimmune hemolysis;

• neuropsychiatric: delirium, psychosis, seizure;

• mucocutaneous: nonscarring alopecia, oral ulcers, subcutaneous or discoid lupus, acute cutaneous lupus;

• serosal: pleural or pericardial effusion, acute pericarditis;

• musculoskeletal: joint involvement; and

• renal: proteinuria >0.5g/24h, renal biopsy class II or V lupus nephritis, renal biopsy class III or IV nephritis.

Immunologic domains and criteria include the following:

• positive antiphospholipid antibodies: anticardiolipin antibodies, antibeta-2 glycoprotein 1 antibodies, lupus anticoagulant;

• complement protein: low C3 or C4, low C3 and C4; and

• SLE-specific antibodies: anti-dsDNA antibody or anti-S.

Treatment and Management
While there is no cure for lupus, there are medications that can help reduce its severity (prevent organ damage) and manage symptoms.

NSAIDs
NSAIDs (eg, naproxen, celecoxib) reduce inflammation in lupus, but older patients have higher risks of adverse drug reactions, including gastrointestinal bleeding, increased cardiovascular events, and kidney injury. Older adults should receive the lowest dose possible and should be monitored closely for these potential complications.

Antimalarial Medications
The antimalarial drug hydroxychloroquine is commonly used in late-onset SLE to reduce disease activity and prevent flares by modulating the immune response in older adults, especially those with milder forms of the disease. It’s been shown to be effective in decreasing pain and swelling and preventing joint damage while improving the overall quality of life for these patients. Side effects include nausea, hair loss, and increased risk of infection. However, the benefits often outweigh the risks for many patients. Routine eye exams are required as long-term use can cause retinal damage. There’s an increased risk of drug-drug interactions with hydroxychloroquine in older adults, and it should be used with caution when using drugs that prolong QT interval.

Corticosteroids
Corticosteroids such as prednisone are very effective in reducing the swelling, warmth, pain, and tenderness associated with lupus inflammation. However, they can also increase atherosclerosis and cardiovascular risks, gastrointestinal ulcers and bleeding, osteoporosis, and fracture risk, and decrease immune response. Their use should generally be reserved for when NSAIDs and antimalarials are insufficient to control lupus.

Immunosuppressive Medications
Immunosuppressive medications are used to control more serious lupus activity that affects major organs, including the kidney, brain, cardiovascular system, and lungs. These medications help suppress the overactive immune system and reduce inflammation. Possible side effects include increased infection risk. Patients may also need to avoid live virus vaccines, and inactivated vaccines will likely be less effective.

DHEA (Dehydroepiandrosterone)
DHEA is a mild male hormone that’s effective in treating lupus symptoms like hair loss, joint pain, fatigue, and cognitive dysfunction. It can also help with osteoporosis. Side effects include acne, facial hair growth, oily skin, excessive sweating, lower HDL (good cholesterol) production, and increased estrogen levels in postmenopausal women.

Lifestyle Modifications
Wearing sun-protective attire and minimizing time in the sun can assist in symptom control and minimizing flares. It’s also crucial to prioritize the management of stress.

Summary
Late-onset SLE presents unique challenges in diagnosis and management. Health care professionals should be aware of the atypical presentation of lupus in older adults. By being vigilant in considering the possibility of lupus in older adults, they can help ensure timely diagnosis and treatment of this population, which is crucial for improving their quality of life and overall health outcomes.

— Mark D. Coggins, PharmD, BCGP, FASCP, is a long term care expert and corporate pharmacy consultant for Touchstone-Communities, a leading provider of senior care that includes skilled nursing care, memory care, and rehabilitation for older adults throughout Texas. He’s a past director of the American Society of Consultant Pharmacists and was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the Excellence in Geriatric Pharmacy Practice Award.

References
1. Lupus facts and statistics. Lupus Foundation of America website. https://www.lupus.org/resources/lupus-facts-and-statistics. Accessed June 24, 2024. Updated July 23, 2021.

2. Pons-Estel GJ, Alarcón GS, Scofield L, Reinlib L, Cooper GS. Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum. 2010;39(4):257-268.

3. Does lupus occur in men? Lupus Foundation of America website. https://www.lupus.org/resources/does-lupus-occur-in-men. Accessed June 24, 2024. Updated June 1, 2020.

4. Burgos PI, Alarcón, GS. Late-onset lupus: facts and fiction. Future Rheumatology. 2008;3(4):351-356.

5. Gómez J, Suárez A, López P, Mozo L, Díaz JB, Gutiérrez C. Systemic lupus erythematosus in Asturias, Spain: clinical and serologic features. Medicine (Baltimore). 2006;85(3):157-168.

6. Weckerle CE, Niewold TB. The unexplained female predominance of systemic lupus erythematosus: clues from genetic and cytokine studies. Clin Rev Allergy Immunol. 2011;40(1):42-49.

7. Hasan B, Fike A, Hasni S. Health disparities in systemic lupus erythematosus-a narrative review. Clin Rheumatol. 2022;41(11):3299-3311.

8. Somers EC, Marder W, Cagnoli P, et al. Population-based incidence and prevalence of systemic lupus erythematosus: the Michigan Lupus Epidemiology and Surveillance program. Arthritis Rheumatol. 2014;66(2):369-378.

9. Vaughn SE, Kottyan LC, Munroe ME, Harley JB. Genetic susceptibility to lupus: the biological basis of genetic risk found in B cell signaling pathways. J Leukoc Biol. 2012;92(3):577-591.

10. Touil H, Mounts K, De Jager PL. Differential impact of environmental factors on systemic and localized autoimmunity. Front Immunol. 2023;14:1147447.

11. Woo JMP, Parks CG, Jacobsen S, Costenbader KH, Bernatsky S. The role of environmental exposures and gene-environment interactions in the etiology of systemic lupus erythematous. J Intern Med. 2022;291(6):755-778.

12. Mak A, Tay SH. Environmental factors, toxicants and systemic lupus erythematosus. Int J Mol Sci. 2014;15(9):16043-16056.

13. Kim JW, Kim HA, Suh CH, Jung JY. Sex hormones affect the pathogenesis and clinical characteristics of systemic lupus erythematosus. Front Med (Lausanne). 2022;9:906475.

14. Kim JW, Jung JY, Kim HA, Yang JI, Kwak DW, Suh CH. Lupus low disease activity state achievement is important for reducing adverse outcomes in pregnant patients with systemic lupus erythematosus. J Rheumatol. 2021;48:707-716.

15. Jones JM, Jørgensen TN. Androgen-mediated anti-inflammatory cellular processes as therapeutic targets in lupus. Front Immunol. 2020;11:1271.

16. Lupus symptoms. Lupus Foundation of America website. https://www.lupus.org/resources/common-symptoms-of-lupus. Accessed July 3, 2024. Updated July 25, 2023.

17. Lupus and brain fog. Lupus Foundation of America website. https://www.lupus.org/resources/lupus-and-brain-fog. Accessed July 3, 2024. Updated November 18, 2021.

18. Riveros FA, Holgado S, Sanvisens BA, et al. Late-onset versus early-onset systemic lupus: characteristics and outcome in a national multicentre register (RELESSER). Rheumatology (Oxford). 2021;60(4):1793-1803.

19. Lalani S, Pope J, de Leon F, Peschken C; Members of CaNIOS/1000 Faces of Lupus. Clinical features and prognosis of late-onset systemic lupus erythematosus: results from the 1000 faces of lupus study. J Rheumatol. 2010;37(1):38-44.

20. Kernder A, Richter JG, Fischer-Betz R, et al. Delayed diagnosis adversely affects outcome in systemic lupus erythematosus: cross sectional analysis of the LuLa cohort Lupus. 2021;30:431-438.

21. Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheumatol. 2019;71(9):1400-1412.