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Fatigue in SLE: Mitochondrial, Not Structural?

The physical fatigue that plagues many patients with systemic lupus erythematosus (SLE) did not appear to result from structural abnormalities in skeletal muscle, although some mitochondrial dysfunction in the calf muscle was observed, a multimodal MRI study found.

Earlier histologic findings on biopsies suggested that patients with SLE more often had structural abnormalities in the quadriceps muscle group than did healthy controls, but novel MRI techniques such as diffusion tensor imaging and T2 mapping have failed to corroborate this, according to Neil Basu, MD, PhD, of the Institute of Infection, Immunology, and Inflammation at the University of Glasgow in Scotland, and colleagues.

Rather, phosphocreatine recovery (PCr) half time, a marker of mitochondrial dysfunction and changes in metabolic activity, was significantly longer in patients with SLE compared with healthy controls (33 vs 27.1 seconds, P=0.045), the researchers reported online in Arthritis Care & Research.

Fatigue is one of the most problematic aspects of their disease, report patients with SLE, contributing significantly to lower quality of life and disability — yet it remains little understood or appreciated.

“Patients [with SLE] describe multiple dimensions of fatigue and therefore its etiology is likely to be complex,” and could involve both peripheral and central mechanisms. “Developments in MRI technology offer a noninvasive opportunity to comprehensively quantify skeletal muscle pathology at both metabolic and structural levels,” Basu and colleagues explained.

To explore this, they enrolled 19 patients with SLE and 18 healthy controls, who were mostly women and whose mean age was 43. Patients were required to have at least 3 months of a score above 3 on the Chalder Fatigue Scale, have impaired muscle strength, and inactive SLE. Multiple MRI images of the thickest part of the right calf were obtained and analyzed.

Compared with controls, the cases had significantly more physical fatigue on the Chalder Fatigue Scale (14.7 vs 6.9, P<0.0001), pain on the 0-10 numeric rating scale (3.5 vs 0.3, P<0.0001), sleep disturbances on the Jenkin's Sleep Scale (12.7 vs 4.8, P<0.0001), anxiety on the Hospital Anxiety and Depression Scale (9.3 vs 4.3, P=0.0001), and depression on the same scale (6.7 vs 1.6, P<0.0001).

In general, patients had mild disease, with a mean score of 0.11 on the criteria of the Systemic Lupus International Collaborating Clinics and predominantly cutaneous and musculoskeletal disease manifestations. Only one had a history of renal disease.

The most common medications used were hydroxychloroquine and methotrexate, and only three were on long-term corticosteroids.

On the following structural parameters, no significant differences were detected between cases and controls:

  • Mean diffusivity (x 10-3 mm2 per sec), 1.57 vs 1.54, P=0.401
  • Radial diffusivity (x 10-3 mm2 per sec), 1.39 vs 1.38, P=0.554
  • Fractional anisotropy, 0.21 vs 0.21, P=0.234
  • T2, 33.2 vs 32.6 ms, P=0.185
  • Fat fraction 3.69% vs 3.90%, P=0.706
  • Muscle cross sectional area, 21.8 vs 22.6 cm2, P=0.623

In addition, although PCr half time was significantly longer among SLE patients compared with controls, correlations were not seen for this finding with either physical fatigue (r =-0.28, 95% CI -0.60 to 0.13, P=0.25) or mental fatigue (r = 0.2, 95% CI -0.21 to 0.54, P=0.41).

“Taken together, skeletal muscle does not appear to serve as a major factor in SLE-related fatigue,” the researchers observed.

“If not skeletal muscles, what then are the main explanations of physical fatigue among SLE patients?” they asked.

They pointed to a recent study in a different multisystem autoimmune condition — antineutrophil cytoplasmic antibody-associated vasculitis — in which fatigue did not correlate with skeletal muscle mass or function. Rather, affected individuals had lower levels of voluntary activation of muscle, reduced maximal voluntary muscle contraction, and increased levels of perceived exertion. “Together, these observations pointed towards centrally rather than peripherally driven mechanisms,” they stated.

They concluded that future investigations into SLE-associated fatigue should focus on mechanisms in areas other than skeletal muscle. “Learning from other chronic diseases, the investigation of central mechanisms using advanced MRI brain techniques appears to offer greater potential.”

Limitations of the study included participants’ generally mild disease and its strict eligibility criteria.

The study was supported by Lupus U.K.

One co-author is an employee of GlaxoSmithKline.