Cachexia in Systemic Lupus Erythematosus: Risk Factors and Relation to Disease Activity and Damage

Abstract

Objective

Cachexia is a disorder characterized by involuntary weight loss in addition to loss of homeostatic control of both energy and protein balance. Despite an abundance of data from other inflammatory diseases, cachexia in SLE remains a largely undescribed syndrome.

Methods

2406 patients in a prospective SLE cohort had their weight assessed at each visit. Patients were categorized into five predetermined groups based on weight. Cachexia was defined based on modified Fearon criteria (5% stable weight loss in 6 months without starvation relative to the average weight in all prior visits AND/OR weight loss >2% without starvation relative to the average weight in all prior cohort visits and a BMI <20). Risk of cachexia within 5 years of cohort entry was based on Kaplan Meier estimates. The association of prior disease manifestations with risk of cachexia adjusted by current steroid use was determined using Cox regression. An analysis of variance test was used to determine whether SLICC/ACR Damage Index scores varied based on cachexia status.

Results

Within five years of cohort entry, 56% of patients developed cachexia, 18% of which never recovered their weight during follow up. The risk factors for cachexia development were BMI<20, current steroid use, vasculitis, lupus nephritis, serositis, hematologic, positive anti-dsDNA, anti-Sm, and anti-RNP. Patients with intermittent cachexia had significantly higher SLICC/ACR Damage Index compared to those with continuous cachexia or without cachexia.

Conclusion

Cachexia is an underrecognized syndrome in patients with SLE. SLE patients with intermittent cachexia have the highest risk of future organ damage.

Weight loss is a common manifestation in SLE with an incidence ranging between 17– 51% in a large series ¹. The extent of weight loss is generally described as being less than 10% and it usually precedes the diagnosis of SLE ². Since it is so common, several disease activity indices record weight loss. The BILAG index records both anorexia and unintentional weight loss (>5%) under constitutional or general features ³. In the SLAM-R Index ⁴, weight loss can be recorded as mild if less than 10% of preexisting body weight, and severe if greater than 10% of body weight. On the other hand, SLEDAI and ECLAM do not record weight loss².

Cachexia is a disorder characterized by involuntary weight loss in addition to loss of homeostatic control of both energy and protein balance⁵. It is distinct from starvation and simple malnutrition which are readily reversible by the provision of adequate nutrients. It has been described in an entire range of disorders including malignant disease, heart failure, renal disease, chronic obstructive pulmonary disease, neurological disease, AIDS, and rheumatoid arthritis⁶. Cachexia has been shown to lead to progressive functional impairment, treatment-related complications, poor quality of life, and increased mortality⁷.

Cachexia is formally defined based on two sets of criteria: the Fearon and Evans criteria^8–10. Fearon criteria are defined as 5% stable weight loss in 6 months without starvation AND/OR weight loss >2% and BMI <20 AND/OR appendicular skeletal muscle index consistent with sarcopenia (males <7.26 kg/m2; females <5.45 kg/m2) and any degree of weight loss >2%⁸. The Evans criteria are defined as 5% weight loss in past 12 months OR BMI <20 with CRP>5mg/L, hemoglobin <12g/dL, albumin <3.2g/dL, fatigue, anorexia, and decreased muscle strength⁸.

Despite an abundance of data from other inflammatory diseases, cachexia in systemic lupus erythematosus remains a largely undescribed syndrome, despite the observation that weight loss is common. We thus sought to define the prevalence of cachexia in SLE and to identify the main factors that place patients at risk of developing cachexia.

Methods

As previously described ¹¹, the Hopkins Lupus Cohort is a prospective cohort study of predictors of lupus flare, atherosclerosis, and health status in SLE. The study cohort includes all patients at the Hopkins Lupus Center who have a clinical diagnosis of SLE and give informed consent to participate in the study. Subjects enrolled in the cohort are followed quarterly or more frequently if clinically necessary. The clinical features, laboratory testing, and damage accrual data are recorded at the time of entry into the cohort and are updated at subsequent visits. The Hopkins Lupus Cohort has been approved by the Johns Hopkins University School of Medicine Institutional Review Board and complies with the Health Insurance Portability and Accountability Act. All patients gave written informed consent.

Ninety-five percent of patients fulfilled 4 or more of the American College of Rheumatology (ACR) 1982 revised classification criteria for SLE ^12,13 and the SLICC classification criteria for SLE ¹⁴. Disease activity was measured with the SELENA revision of the Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index instrument score ¹⁵ and the Physician Global Assessment ¹⁶.

Patients with malignancy, severe renal failure (glomerular filtration rate <20 ml/min), chronic liver disease, and diabetes mellitus were excluded from the study. Visits at which patients were pregnant were excluded from the analyses.

2452 adult patients (>18 years old) who had their weight assessed at each visit were included in the study. Weight was measured at each clinic visit with the participant wearing light indoor clothes without shoes and using a high-quality, calibrated digital scale. Height was measured once at cohort entry using a calibrated, wall-mounted stadiometer.

Mean follow up was 7.75 years (SD=6.85). Patients were recruited between April 1987 and June 2016. The average number of weight measurements per person was 23.97 (SD=17.3)

Patients were categorized into five predetermined groups based on weight: low (body mass index (BMI)<20 kg/m2), normal weight (reference, BMI 20–24.9 kg/m2), overweight (25–29.9 kg/m2), obese (BMI 30–34.9 kg/m2), and severely obese (BMI>35 kg/m2).

Cachexia was defined based on modified Fearon criteria as 5% stable weight loss in 6 months without starvation relative to the average weight in all prior cohort visits AND/OR weight loss >2% without starvation relative to the average weight in all prior cohort visits and a BMI <20. Evans criteria could not be used due to lack of data.

The overall proportion of participants who developed cachexia per the Fearon criteria within 5 years was estimated using Kaplan Meier survival analysis. The percentage of participants that regained their original weight within 12 months and 5 years following their cachexia diagnosis was calculated and defined as “intermittent cachexia.” Those participants that never regained their original weight were classified as having “continuous cachexia.”

The association of prior disease manifestations with risk of cachexia adjusted by current corticosteroid use was determined using Cox regression. An analysis of variance test was used to determine whether the SLICC/ACR Damage Index scores varied based on whether participants never had cachexia, had intermittent cachexia, or had continuous cachexia based on the Fearon criteria.

Results

The risk of cachexia development within the first 5 years of cohort entry based on Kaplan Meyer estimates is presented in table 1. Fifty-six percent of patients met Fearon criteria. As displayed in table 2, 34% of participants that developed cachexia recovered within 12 months, while 45.6% recovered by the end of the study period. Eighteen percent of participants remained cachectic at the end of study period.

Table 1.

Risk of cachexia (FEARON criteria) within 5 years of cohort entry

Patient Characteristic	Risk of Cachexia (Fearon) within 5 years of cohort entry (95% CI)	P-value for difference by patient characteristic
All (n=2,286)	56.3% (54.3%, 58.4%)
Age Group		0.73
<30 (n=751)	58% (53%, 62%)
30–44 (n=920)	56% (47%, 58%)
45–59 (n=492)	53% (47%, 58%)
60+ (n=123)	59% (48%, 69%)
Race		0.03
White (n=1,209)	53.9% (51.1%, 56.7%)
Black (n=908)	58.8% (55.6%, 62.0%)
Asian (n=87)	58.6% (47.9%, 68.6%)
Other (n=82)	62.2% (51.1%, 72.1%)
Sex		0.37
Female (n=2266)	56.5% (54.3%, 58.6%)
Male (n=186)	54.3% (46.8%, 61.7%)
Initial BMI		<0.001
<20 (n=194)	73.2% (66.5%, 79.0%)
20–24.9 (n=690)	56.7% (52.9%, 60.3%)
25–29.9 (n=564)	58.5% (54.3%, 62.5%)
30+ (n=838)	50.7% (47.3%, 54.1%)
Steroid Use		<0.001
None	52.4% (49.6%, 55.2%)
Current Steroid Use	61.1% (58.1%, 64.0%)
Antibody Profiles
Anti ds-DNA (n=856)	59.8% (57.3%, 62.3%)	<0.01
Anti-Smith (n=307)	66.3% (61.9%, 70.5%)	<0.001
ANA (n=1251)	56.7% (54.6%, 58.8%)	0.38
Anti-La (n=179)	62.8% (57.0%, 68.2%)	0.03
Anti-RNP (n=405)	62.8% (59.0%, 66.4%)	<0.001
Lupus anticoagulant (n=179)	61.2% (58.3%, 64.1%)	0.20
Anti-B2 Glycoprotein (n=279)	65.6% (61.0%, 70.0%)	0.38
Lupus Manifestations (cumulative)
Skin (n=1155)	57.1% (54.9%, 59.2%)	0.38
Musculoskeletal (n=1196)	56.9% (54.7%, 59.0%)	0.78
Renal (n=719)	62.1% (59.3%, 65.9%)	<0.001
Hematologic (n=1116)	58.7% (56.4%, 60.9%)	<0.001
Serositis (n=934)	60.5% (58.1%, 63.0%)	<0.01
CNS (n=830)	60.4% (57.8%, 63.0%)	0.13
Vasculitis (n=221)	67.0% (61.7%, 71.9%)	<0.001

Table 2.

Cachexia resolution using Fearon Criteria over the 12 months following diagnosis and over the entire study period:

Cachexia Resolution	Number of patients at 12 months	Percent (%) at 12 months	Number of patients over entire study period	Percent (%) over entire study period
Never Diagnosed with Cachexia	832	36.4%	832	36.4%
Intermittent (Resolved)	777	34.0%	1,043	45.6%
Continuous (Never Resolved)	677	29.6%	411	18.0%
Total	2,286	100.0%	2,286	100.0%

The main risk factors for cachexia development were BMI<20 at cohort entry, current corticosteroid use, vasculitis, lupus nephritis, serositis, hematologic manifestations, positive anti-dsDNA, anti-Sm, and anti-RNP.

The rate ratio comparing those with prior disease manifestations to those without with respect to the incidence of cachexia is presented in table 3. Lupus nephritis (p<0.001), vasculitis (p<0.001), serositis (p<0.05), and hematologic (p<0.01) lupus were significantly associated with the development of cachexia (p<0.001) after adjustment for prednisone use.

Table 3:

Rate ratio comparing those with prior disease manifestation to those without with respect to incidence of cachexia

Prior Disease Manifestation	Crude Rate Ratio (95% CI)	P-value	Adjusted Rate Ratio* (95% CI)	P-value
Skin	1.08 (0.90, 1.30)	0.38	1.10 (0.92, 1.31)	0.32
Musculoskeletal	1.03 (0.83, 1.27)	0.78	1.01 (0.81, 1.25)	0.93
Serositis	1.22 (1.08, 1.38)	0.001	1.15 (1.01, 1.30)	0.03
Neurologic	1.09 (0.97, 1.22)	0.13	1.07 (0.96, 1.20)	0.23
Renal	1.42 (1.27, 1.58)	<0.001	1.33 (1.19, 1.49)	<0.001
Hematologic	1.32 (1.13, 1.56)	0.001	1.26 (1.07, 1.48)	0.01
Vasculitis	1.36 (1.18, 1.57)	<0.001	1.28 (1.11, 1.48)	0.001
Constitutional	1.00 (0.78, 1.29)	0.97	1.40 (1.25, 1.56)	<0.001

^*Adjusted by current steroid use

Table 4 presents the rate ratio comparing those with disease activity in the preceding 3 months as measured by SELENA SLEDAI to those without, with respect to the incidence of cachexia. Only the presence of renal activity was significantly associated with cachexia development.

Table 4.

Rate ratio comparing those with recent activity to those without with respect to incidence of cachexia

Disease Activity in preceding 3 months as measured by components of SLEDAI	Rate Ratio (95% CI)	P-value
Skin activity	1.1 (0.9, 1.3)	0.25
Musculoskeletal activity	0.9 (0.8, 1.1)	0.51
Renal activity	1.3 (1.1, 1.5)	0.0048
Hematologic Activity	0.9 (0.7, 1.1)	0.34
Serositis Activity	1.2 (0.9, 1.7)	0.20
CNS activity	0.9 (0.6, 1.3)	0.53
Vasculitis Activity	1.2 (0.7, 1.9)	0.52
Constitutional Activity	1.3 (0.6, 2.9)	0.44

Table 5 compares future organ damage as measured by the SLICC/ACR Damage Index between patients with continuous cachexia, intermittent cachexia, and those that never develop cachexia. Patients with intermittent cachexia were more likely to develop cataracts (p<0.001), retinal change or optic atrophy (p<0.01), cognitive impairment (p<0.01), cerebrovascular accidents (p<0.01), cranial or peripheral neuropathy (p<0.001), pulmonary hypertension (p<0.001), pleural fibrosis (p<0.001), angina OR coronary artery bypass (p<0.05), infarction or resection of bowel (p<0.05), deforming or erosive arthritis (p<0.001), osteoporosis (p<0.001), avascular necrosis (p<0.001), and premature gonadal failure (p<0.05). Patients with continuous cachexia were more like to have an eGFR<50 (p<0.01), proteinuria >3.5gr/day (p<0.05), and end stage renal disease (p<0.05). Patients who never developed cachexia were less likely to develop malignancy (p<0.01), diabetes (p<0.05), valvular disease (p<0.05), and cardiomyopathy (p<0.001),

Table 5.

SLICC Damage Index in patients with continuous cachexia, intermittent cachexia, and those without cachexia

Item (n=2,455)	Never SLICC Score (Mean ± SD)	Intermittent SLICC Score (Mean ± SD)	Continuous SLICC Score (Mean ± SD)	p-value
Ocular
Any cataract ever	0.12 ± 0.33	0.25 ± 0.43	0.16 ± 0.37	p<0.001
Retinal change OR optic atrophy	0.03 ± 0.16	0.06 ± 0.24	0.04 ± 0.19	p=0.01
Neuropsychiatric
Cognitive impairment	0.05 ± 0.21	0.09 ± 0.29	0.07 ± 0.25	p=0.01
Seizures	0.05 ± 0.21	0.03 ± 0.18	0.05 ± 0.22	p=0.05
Cerebrovascular accident ever	0.08 ± 0.31	0.12 ± 0.38	0.07 ± 0.29	p=0.01
Cranial/peripheral neuropathy	0.06 ± 0.23	0.13 ± 0.33	0.07 ± 0.26	p<0.001
Transverse myelitis (p=0.14)	0.01 ± 0.05	0.01 ± 0.10	0.01 ± 0.10	p=0.14
Renal
eGFR <50	0.05 ± 0.21	0.06 ± 0.24	0.09 ± 0.29	p=0.01
Proteinuria >=3.5 gm/day	0.07 ± 0.26	0.08 ± 0.27	0.12 ± 0.32	p=0.02
Or
End-stage renal disease	0.11 ± 0.57	0.15 ± 0.65	0.22 ± 0.78	p=0.02
Pulmonary
Pulmonary hypertension	0.03 ± 0.16	0.07 ± 0.25	0.05 ± 0.22	p<0.001
Pulmonary fibrosis	0.06 ± 0.24	0.10 ± 0.30	0.06 ± 0.23	p=0.01
Shrinking lung	0.01 ± 0.06	0.01 ± 0.08	0 ± 0	p=0.28
Pleural fibrosis	0.01 ± 0.12	0.05 ± 0.21	0.02 ± 0.13	p<0.001
Pulmonary infarction	0.01 ± 0.06	0.01 ± 0.08	0.01 ± 0.09	p=0.60
Cardiovascular
Angina OR coronary artery bypass	0.03 ± 0.16	0.05 ± 0.22	0.04 ± 0.19	p=0.03
Myocardial infarction ever
Cardiomyopathy	0.04 ± 0.22	0.05 ± 0.24	0.06 ± 0.26	p=0.34
Valvular disease	0.02 ± 0.13	0.04 ± 0.20	0.05 ± 0.23	p<0.001
Pericarditis OR pericardiectomy	0.02 ± 0.13	0.04 ± 0.19	0.03 ± 0.16	p=0.03
	0.01 ± 0.12	0.02 ± 0.13	0.03 ± 0.17	p=0.18
Peripheral vascular
Claudication for 6 months	0.01 ± 0.11	0.02 ± 0.13	0.01 ± 0.12	p=0.64
Minor tissue loss	0.01 ± 0.05	0.01 ± 0.09	0.02 ± 0.13	p=0.02
Significant tissue loss	0.01 ± 0.12	0.02 ± 0.19	0.01 ± 0.09	p=0.04
Venous thrombosis	0.05 ± 0.21	0.03 ± 0.18	0.03 ± 0.18	p=0.27
Gastrointestinal
Infarction or resection of bowel	0.13 ± 0.39	0.17 ± 0.41	0.13 ± 0.38	p=0.04
Mesenteric insufficiency	0.01 ± 0.05	0.01 ± 0.08	0 ± 0	p=0.20
Chronic peritonitis	0.01 ± 0.05	0.01 ± 0.06	0.01 ± 0.07	p=0.76
Stricture OR upper GI tract surgery	0.01 ± 0.09	0.01 ± 0.09	0.02 ± 0.14	p=0.11
Musculoskeletal
Muscle atrophy or weakness	0.02 ± 0.15	0.03 ± 0.18	0.01 ± 0.11	p=0.08
Deforming or erosive arthritis	0.04 ± 0.20	0.09 ± 0.28	0.06 ± 0.24	p<0.001
Osteoporosis	0.07 ± 0.25	0.19 ± 0.39	0.09 ± 0.29	p<0.001
Avascular necrosis	0.13 ± 0.45	0.22 ± 0.55	0.12 ± 0.43	p<0.001
Osteomyelitis	0.01 ± 0.08	0.01 ± 0.09	0.01 ± 0.05	p=0.44
Skin
Scarring chronic alopecia	0.03 ± 0.20	0.05 ± 0.21	0.04 ± 0.21	p=0.86
Extensive scarring or panniculum	0.01 ± 0.12	0.03 ± 0.18	0.02 ± 0.14	p=0.04
Skin ulceration	0.01 ± 0.10	0.02 ± 0.13	0.01 ± 0.09	p=0.26
Premature gonadal failure	0.03 ±0.18	0.06 ±0.24	0.03 ±0.18	p=0.02
Diabetes	0.06 ±0.24	0.09 ±0.29	0.09 ±0.29	p=0.04
Malignancy	0.09 ±0.30	0.14 ±0.38	0.15 ±0.38	p=0.01
Total	1.57 ±2.14	2.67 ±2.69	2.12 ±2.59	p<0.001

^*Continuous cachexia defined as cachexia persisting within 12 months of original diagnosis vs. intermittent cachexia is defined as recovery within 12 months of original diagnosis

Conclusion

It is tempting to draw a parallel between cachexia in SLE and cancer cachexia. Within five years of cohort entry, more than 50% of the Hopkins Lupus cohort patients developed cachexia as defined by Fearon criteria. In comparison, Dewys et al. ¹⁷ reported a cachexia prevalence of 54% among 3047 patients with cancer enrolled in 12 chemotherapy protocols. The reported prevalence of cachexia by cancer site is 48.9% for head and neck, 34% for leukemia/lymphoma, 45.3% for lung, 39.3% for colon/rectum, 66.7% for pancreas, 20.5% for breast, and 13.9% for prostate ¹⁸. The prevalence of cachexia in SLE was thus comparable to that reported in cancer. In contrast to cancer-related cachexia, a large proportion of SLE patients (45.6%) recover their previous weight, but 18% of SLE patients remain cachectic throughout their follow up. This high recovery rate may be attributable to improved disease activity and decreased systemic inflammation, a concept that remains controversial in cancer-related cachexia ¹⁹.

Development of cachexia was significantly more likely among those with BMI<20, current steroid use, vasculitis, lupus nephritis, serositis, hematologic lupus, positive anti-dsDNA, anti-Sm, and anti-RNP. After adjustment for prednisone use, only patients with musculoskeletal, skin, and neurologic manifestations were not at risk of developing cachexia, indicating a broad correlation with different disease manifestations.

SLE patients with continuous cachexia were more likely to have renal damage (eGFR<50, ESRD, proteinuria >=3.5 gm/day). In contrast, patients with intermittent cachexia were at higher risk of damage across the board, with a significantly higher risk of avascular necrosis, osteoporosis, erosive or deforming arthritis, cardiomyopathy, pulmonary hypertension, pleural fibrosis, and cataracts.

The mechanisms underlying the cachexia phenomenon in SLE have not been previously studied, but there are extensive data from basic and clinical cancer studies that may be relevant to SLE. Tumors secrete a range of pro-cachexia factors thought to be unique to cancer-related cachexia and colloquially termed the ‘tumor secretome’⁵. Pro-inflammatory mediators of cachexia arising from tumor-immune system cross-talk include IL-6, IL-1, tumor necrosis factor (TNF), IFNγ, TRAF6, Il-11, Il-17, oncostatin M, and TNF-related weak inducer of apoptosis (TWEAK; also known as TNFSF12) ⁵. Every single pro-inflammatory cytokine mentioned as part of the tumor secretome has a role in lupus pathogenesis: failure in the inhibition of IL-1 activation is a critical event in the active stages of SLE ²⁰; increased serum level of TNF-α is observed in SLE patients and is associated with disease activity²¹; IL-6 plays a critical role in B cell hyperactivity and pathophysiology of human SLE²²; IFN-gamma hyperproduction is required for lupus development, presumably by increasing MHC expression and autoantigen presentation to otherwise quiescent nontolerant anti-self T cells ²³; TRAF6 is associated with SLE ²⁴; and raised levels of urinary and serum soluble TWEAK correlate with renal disease activity in patients with lupus nephritis ²⁵. This suggests that there may be a common pathway leading to cachexia across different chronic diseases and that the mechanism may not be unique to the tumor secretome. The lower risk of cachexia in patients with skin and musculoskeletal manifestations of lupus could potentially be explained by mechanistic differences and activation of different pathways that may have an opposite effect on catabolism.

It is known that cancer cachexia has a negative effect on quality of life, physical function, treatment tolerance, and overall mortality, with cachexia being the cause of death in 30% of cancer patients ²⁶ but the effect of cachexia on physical function, wellbeing, and other measures of quality of life in SLE is unknown and requires further study.

Paradoxically, the main shortcoming of our study includes the use of body mass index as a measure of weight since BMI is a rather poor indicator of percent of body fat ²⁷ and does not distinguish between individuals who may have metabolic syndrome or visceral adiposity, yet develop sarcopenia. Gained weight may consist of functional muscle mass, but it may also be composed largely of fat or of additional water in the form of edema, ascites, or pleural effusion ²⁸. Ideally, cachexia would be defined as sarcopenia based on body composition evaluation with a dual x-ray absorptiometry (DXA).

In conclusion, cachexia is an under recognized syndrome in SLE affecting a large proportion of patients, but which is irreversible in only 18% of patients. Those with persistent cachexia tend to have a higher risk of renal damage, while patients with intermittent cachexia are at a higher risk of damage in all remaining organ systems. Further studies are needed to elucidate the implications of cachexia in terms of the response to treatment, long term outcomes, quality of life, as well as its role as a potential cardiovascular risk factor in SLE.

Significance and Innovations.

• Cachexia is an underrecognized syndrome in patients with SLE affecting more than 50% of patients.

• Most SLE patients recover their previous weight over time, but 18% of patients have continuous cachexia.

• The risk factors for cachexia development were BMI<20, current steroid use, vasculitis, lupus nephritis, serositis, hematologic lupus, positive anti-dsDNA, anti-Sm, and anti-RNP.

• SLE patients with intermittent cachexia have significantly higher risk for future organ damage compared to patients without cachexia and those with continuous cachexia.