The commentary, authored by Lotte Habermann-Horstmeier of the Villingen Institute of Public Health in Germany, does not present new experimental data. Instead, it offers something arguably more valuable at this stage of the field: a structured, testable framework. Drawing on a targeted synthesis of literature from PubMed and Web of Science, the author sorts evidence into three categories—direct SLE findings, findings from ME/CFS research, and cross-condition mechanistic inference—and insists that these be kept rigorously separate. The result is a hypothesis-generating proposal for an SLE–ME/CFS research phenotype, a defined subgroup of lupus patients whose symptoms persist for at least six months, worsen after exertion, and include unrefreshing sleep, cognitive symptoms, or orthostatic intolerance, once alternative explanations and comorbidities have been systematically excluded.

The clinical rationale for such a phenotype rests on a well-documented gap between conventional disease measures and patient experience. In lupus, indices of inflammatory activity often normalize under treatment, yet patient-reported outcomes tell a different story. Fatigue ranks among the most prevalent and disabling complaints across the disease course, and studies of patients in remission have repeatedly documented impaired physical function, reduced exercise capacity, sleep disturbance, and neurocognitive symptoms that conventional lupus metrics fail to capture. This discordance has practical consequences: patients whose laboratory values look reassuring may nonetheless be functionally limited, and clinicians lack a framework for understanding—or investigating—why.

What makes the proposed phenotype more than a descriptive label is the mechanistic scaffolding beneath it. The commentary assembles direct evidence from lupus research pointing to several interacting biological systems. Residual immune activation persists in many patients despite apparent disease control, with ongoing immune cell activation and inflammatory signaling detectable below the threshold captured by clinical indices. Oxidative stress, an imbalance between reactive oxygen species and antioxidant defenses, has been documented in SLE and can damage cellular components ranging from lipids to DNA. Mitochondrial alterations—the dysfunction of the organelles that generate cellular energy—have likewise been reported, offering a plausible route from biochemical injury to the fatigue and exercise intolerance patients describe.

Vascular and autonomic mechanisms form a second pillar of the framework. Endothelial dysfunction, a impairment of the blood vessels’ inner lining that precedes atherosclerosis, is well established in lupus and contributes to the disease’s elevated cardiovascular risk, but it may also compromise tissue perfusion during exertion and in the brain. Dysautonomia—disordered regulation by the autonomic nervous system—has been described in SLE patients and can produce orthostatic intolerance, the lightheadedness, palpitations, and cognitive dulling that occur when standing disrupts cerebral blood flow. These findings matter because they map directly onto symptoms that dominate the lived experience of the proposed subgroup: exercise that triggers a disproportionate crash, sleep that does not restore, and thinking that falters when upright.

It is here that the commentary’s most provocative move occurs: importing carefully flagged mechanistic insights from ME/CFS research. That field, long marginalized but increasingly rigorous, has accumulated human evidence of impaired cellular energetics, with studies suggesting that energy metabolism in patient cells behaves abnormally under stress; of autonomic dysfunction measurable in the clinic; of altered cerebral perfusion on neuroimaging; and of neuroimmune dysregulation involving inflammatory signaling that reaches the central nervous system. Post-exertional symptom exacerbation—the hallmark worsening of symptoms hours to days after physical or cognitive effort—serves as the condition’s defining feature and a key anchor for the proposed lupus phenotype. The author is explicit that these ME/CFS findings are hypotheses for lupus, not established facts: they converge plausibly with direct SLE evidence, but they require direct validation in lupus cohorts before any conclusion can be drawn.

The framework’s deliberate non-linearity is one of its distinguishing technical features. Rather than proposing a single causal chain—molecule X causes symptom Y—the author describes interacting immune, metabolic, vascular, autonomic, and neurocognitive mechanisms that may reinforce one another dynamically over time. Mitochondrial dysfunction, for instance, could amplify oxidative stress, which in turn could worsen endothelial function and autonomic regulation, while neuroimmune signaling could sensitize the brain’s fatigue and cognitive circuits. Such feedback structures resist the one-biomarker-one-diagnosis model and instead call for multidimensional phenotyping: simultaneous measurement of immune markers, redox balance, vascular function, autonomic testing, exercise physiology, and neurocognitive performance in the same patients, tracked longitudinally.

Methodological caution runs throughout the proposal. The commentary is explicitly a theoretical, non-systematic synthesis, prioritizing human studies, systematic reviews, meta-analyses, and translational work, and it stops short of defining a new diagnostic entity or a fixed disease trajectory. The proposed phenotype is framed as a research construct—a way to stratify patients for prospective longitudinal studies—rather than a clinical diagnosis. This distinction is important for lupus care, where symptoms such as fatigue and cognitive difficulty can also arise from hypothyroidism, anemia, sleep apnea, depression, medication side effects, or active disease that standard measures miss. The framework therefore requires structured exclusion or assessment of alternative explanations before a patient is classified within the subgroup, mirroring the case-definition discipline developed in ME/CFS research.

If the hypothesis survives prospective testing, the implications could be substantial. A validated SLE–ME/CFS research phenotype would give investigators a stratification tool for clinical trials, separating patients whose persistent symptoms arise from ongoing inflammatory activity from those whose illness follows a different biological path. It could sharpen biomarker discovery by directing attention toward autonomic, endothelial, mitochondrial, and neuroimmune measures rather than conventional serology alone. And it could reshape supportive care, since interventions developed for ME/CFS—pacing strategies to avoid post-exertional crashes, graded approaches to rehabilitation, orthostatic management—might be adapted and formally tested in the lupus subgroup, rather than applied indiscriminately to all patients.

The proposal also carries a message about how medicine handles diseases that fall between specialties. Lupus is the rheumatologist’s territory; ME/CFS remains contested and under-resourced; and patients whose illness straddles the two risk falling into the gap. By articulating a phenotype that borrows mechanistic rigor from one condition to explain unresolved symptoms in the other, the commentary offers a template for hypothesis-driven bridge-building across diagnostic boundaries. The author is careful to frame the work as hypothesis-generating, and the next step—longitudinal, multidimensional studies of lupus patients with persistent symptoms—will determine whether the SLE–ME/CFS research phenotype describes a real biological subgroup or merely a useful way of organizing uncertainty. Either outcome would advance a conversation that many patients, whose suffering persists long after their inflammation has quieted, have been waiting for the field to have.

Subject of Research: Persistent fatigue and related symptoms in long-standing systemic lupus erythematosus and their proposed mechanistic overlap with ME/CFS

Article Title: Persistent symptom burden in long-standing systemic lupus erythematosus: a subgroup-focused hypothesis for an SLE–ME/CFS research phenotype

Article References: Habermann-Horstmeier, L. (2026). Persistent symptom burden in long-standing systemic lupus erythematosus: a subgroup-focused hypothesis for an SLE–ME/CFS research phenotype. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08867-8

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08867-8

Keywords: systemic lupus erythematosus, ME/CFS, chronic fatigue, post-exertional malaise, dysautonomia, endothelial dysfunction, mitochondrial dysfunction, oxidative stress, neuroimmune dysregulation, orthostatic intolerance, disease phenotype, Journal of Translational Medicine

The research team, led by investigators at the Pain & Fatigue Study Center in the Department of Neurology, drew participants from an NIH-funded parent study designed to examine the relationship between cardiopulmonary exercise testing and post-exertional malaise, the hallmark symptom of ME/CFS. Between August 2021 and July 2025, forty-nine adults aged 25 to 60 years who met the 1994 Fukuda case definition completed both assessments. To ensure a substantial current symptom burden, participants were required to report moderate-to-severe ratings on post-exertional malaise and on at least three of seven additional symptoms, including sore throat, headache, myalgia, and unrefreshing sleep. Individuals with medical conditions that could explain the fatigue, including anemia identified by routine laboratory testing, were excluded, as were those taking medications that blunt cardiovascular responses and those with certain psychiatric diagnoses.

The orthostatic assessment relied on the 10-minute lean test, a protocol originally developed by NASA to detect orthostatic intolerance in astronauts returning from spaceflight. After at least ten minutes of supine rest, baseline blood pressure, heart rate, respiratory rate, and end-tidal carbon dioxide were recorded in triplicate at one-minute intervals using a portable capnograph and pulse oximeter. Participants then stood with feet together roughly six to eight inches from a wall and leaned against it without moving for ten minutes, while the same parameters were captured every minute. This test captures several distinct physiological abnormalities: postural orthostatic tachycardia syndrome, defined as a heart rate rise of at least 30 beats per minute or an absolute heart rate of at least 120 beats per minute; supine hypocapnia, defined as any baseline end-tidal carbon dioxide below 34 mmHg; and the postural orthostatic syndrome of hypocapnia, in which carbon dioxide falls below that threshold only upon standing.

Blood volume was measured with the semiautomated Daxor BVA-100 system, a technique regarded as a reference standard for quantitative intravascular volume assessment. After a baseline blood sample was drawn, human serum albumin labeled with iodine-131 was injected intravenously and allowed to equilibrate. Five additional samples were collected at 15, 21, 27, 33, and 39 minutes to correct for the gradual leakage of albumin out of the vasculature, and plasma volume at time zero was extrapolated from at least three samples with a coefficient of variation of no more than 3.9 percent. Total blood volume was calculated as the sum of plasma volume and red blood cell volume, and all values were normalized to each participant’s ideal body size. Total blood volume was then categorized as hypovolemic if it deviated more than 8 percent below the predicted value, normovolemic within 8 percent, and hypervolemic above 8 percent, thresholds consistent with prior ME/CFS blood volume research.

The results painted a picture of remarkable physiological heterogeneity. Seventeen participants, or 35 percent, were classified as hypovolemic, twenty-one as normovolemic, and eleven as hypervolemic. Red blood cell volume told a similar story: nearly half of the cohort, twenty-four participants, had a red cell volume deficit more than 10 percent below ideal, a phenotype that, when routine hemoglobin and hematocrit values are normal, can be considered an occult red cell mass deficit rather than conventional anemia. Yet when the researchers cross-tabulated these volume categories against lean-test outcomes, no significant associations emerged. Fifty-five percent of participants exhibited at least one orthostatic abnormality, with hypocapnic responses proving at least as common as tachycardia: twenty participants showed the postural orthostatic syndrome of hypocapnia, six showed supine hypocapnia, six met criteria for POTS, and four had both POSH and POTS. The distribution of these abnormalities, however, was statistically indistinguishable across hypovolemic, normovolemic, and hypervolemic groups, and the same held true for red blood cell volume categories.

These findings directly confront a body of earlier work. Multiple previous studies have reported reduced total or compartmental blood volumes, smaller cardiac chambers, and diminished stroke volume in subsets of ME/CFS patients, and one pilot study using a dual-isotope technique found lower blood volumes among patients whose day-to-day symptoms suggested orthostatic intolerance. That earlier study, however, relied on clinical history rather than contemporaneous physiological testing, leaving open the possibility that subjective symptom reports and objective orthostatic physiology diverge. By combining quantitative blood volume analysis with a standardized lean test incorporating capnography, the Mount Sinai team demonstrated that even objectively confirmed orthostatic abnormalities do not track with measured volume status. In other words, a patient can be quantitatively hypovolemic yet pass the lean test, or have entirely normal blood volume yet exhibit marked hypocapnia or tachycardia upon standing.

The null result does not mean blood volume is clinically irrelevant. Identifying hypovolemia in an individual patient may still matter, because volume expansion remains a logical therapeutic target for that subgroup. But the new data help explain why pharmacological volume expansion has disappointed in controlled trials: randomized studies of fludrocortisone, a mineralocorticoid that promotes sodium and water retention, showed limited benefit in ME/CFS, implying that correcting hypovolemia alone is often insufficient. The authors argue that orthostatic intolerance in this illness likely arises from multiple converging mechanisms that static volume measurements cannot capture. Among the candidates are impaired venous constriction and excessive venous capacitance, which promote gravitational pooling of blood in the legs; autonomic dysregulation, evidenced by reduced vagal modulation and altered heart rate variability at rest, during sleep, and during orthostatic challenge; and abnormalities of neurohumoral control, including the renin-aldosterone paradox described in POTS and small-fiber neuropathy identified in subsets of patients.

Cerebral perfusion adds another critical dimension. Previous controlled work has shown that upright posture can substantially reduce cerebral blood flow in ME/CFS patients even when heart rate and blood pressure remain within conventional limits, and that this cerebral blood flow reduction during tilt testing is independent of deconditioning as defined by exercise testing. Deconditioning itself, which can reduce plasma volume and ventricular mass over weeks of bed rest, is unlikely to account for the high prevalence of orthostatic intolerance in this population, since patients show greater cerebral blood flow reductions than healthy, sedentary controls. Taken together, these observations support a model in which orthostatic pathology in ME/CFS reflects dynamic failures of autonomic, vascular, respiratory, and cerebral hemodynamic regulation rather than a simple deficit in the amount of blood in the circulation.

The study has limitations that the authors acknowledge candidly. The sample of forty-nine participants, recruited from a single tertiary care center and limited to patients well enough to undergo testing, constrains statistical power and may underrepresent the most severely affected patients. The eight-day interval between the lean test and the blood volume assessment, together with the lack of standardization of acute hydration and salt intake, may have introduced temporal variability in both volume and hemodynamic measures. Anxiety-related hyperventilation and other breathing-pattern abnormalities could not be excluded as contributors to the hypocapnic findings, because state anxiety and tidal volume were not assessed. The 10-minute lean test also imposes milder orthostatic stress than head-up tilt, so hypovolemia-driven instability might conceivably emerge only under more prolonged or severe challenge. The absence of a healthy control group further precluded direct comparison of volume patterns between patients and volunteers.

Even with those caveats, the message for the field is clear and consequential. Orthostatic intolerance was highly prevalent in this cohort, yet neither total blood volume nor red blood cell volume category predicted who would exhibit supine hypocapnia, POSH, or POTS on standardized testing. The authors call for multicenter studies that incorporate dynamic measurements of cerebral blood flow, respiratory pattern, and carbon dioxide regulation during graded orthostatic stress, integrated with blood volume status, to build comprehensive pathophysiological models of the illness. Such phenotype-directed approaches, they argue, will be essential for developing rational therapies that address the actual mechanisms driving orthostatic symptoms, rather than assuming that a single measurable deficit, however intuitively appealing, holds the key to one of ME/CFS’s most disabling features.

Subject of Research: The relationship between measured blood volume, red blood cell volume, and orthostatic intolerance in adults with myalgic encephalomyelitis/chronic fatigue syndrome

Article Title: Total blood volume and red blood cell volume are not associated with orthostatic intolerance in adults with myalgic encephalomyelitis/chronic fatigue syndrome

Article References: Total blood volume and red blood cell volume are not associated with orthostatic intolerance in adults with myalgic encephalomyelitis/chronic fatigue syndrome. (n.d.). https://doi.org/10.14814/phy2.71087

Image Credits: AI Generated

DOI: 10.14814/phy2.71087

Keywords: ME/CFS, orthostatic intolerance, blood volume, red blood cell volume, POTS, hypocapnia, lean test, capnography, autonomic dysfunction, cerebral blood flow, hypovolemia, Physiological Reports