1.

Introduction

Scleroderma, or systemic sclerosis (SSc), is a lifelong condition characterized by vasculopathy, fibrosis of skin and various internal organs, and inflammation or autoimmunity.^1,2 Systemic scleroderma is a rare disorder, with an annual incidence in the United States of about 20 cases per 1 million adults, and a prevalence of 100 to 300 per 1 million population.^3,4 It is more common among women than men, and in certain groups such as Native Americans.^3,4

Limited cutaneous SSc (lcSSc) is part of the heterogeneous group of sclerodermas. LcSSc was formerly known as CREST syndrome in reference to the associated clinical features: calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasias. This connective tissue disease typically has gradual onset and disease expressions are restricted to certain areas of the skin.⁵ In patients with lcSSc, the core manifestations of the disease, including skin calcifications, are mostly confined to the fingers, hands, and forearms distal to the elbows, with or without tightening of the skin of the lower extremities distal to the knees. Cutaneous telangiectasias on the face are also seen, along with varying degrees of internal organ involvement. Proximal extremities and the trunk are not involved. LcSSc may be debilitating and influences a person’s ability to participate in activities of daily life in different ways.^6–8

Although the pathogenesis of this condition is unclear, a number of studies have suggested that the transforming growth factor beta (TGF-$\beta$) is an important candidate in the pathogenic process.^9–12 TGF-$\beta$ is a prototypic profibrotic cytokine that increases collagen synthesis by fibroblasts and downregulates extracellular matrix degradation. Evidence comes from past studies reporting, for instance, a TGF-$\beta$ upregulation, an increase in the expression of TGF-$\beta$ receptors, as well as the observation that the blockade of endogenous TGF-$\beta$ signaling prevents upregulated collagen synthesis in scleroderma fibroblasts.^13–15 TGF-$\beta$ is also known to be involved in immunomodulatory activities. Thus, TGF-$\beta$ appears to be a sound target for therapeutic intervention.^16,17

Interestingly, low-level light therapy (LLLT) with red to near-infrared (NIR) wavelengths has been shown to trigger natural intracellular photobiochemical reactions including TGF-$\beta$ modulation.^18–21 Red to NIR light is thought to be absorbed by mitochondrial respiratory chain components.^22,23 Absorbed light converted to chemical kinetic energy results in the increase of reactive oxygen species and adenosine triphosphate, initiating a signaling cascade which can modulate the expression of growth factors and cytokines.^24–27 Hence, LLLT might be helpful in the treatment of symptoms associated with lcSSc.

This case study was conducted to assess the efficacy of NIR (940 nm) LLLT using millisecond (ms) pulsing and CW on osteoarticular signs and symptoms associated with lcSSc.

2.

Materials and Methods

2.2.

Study Procedures

This was a single-blind within subject case study, where the left forearm was randomly assigned to receive LLLT using sequential pulsing mode and the right forearm assigned to LLLT using a CW mode.

The patient was treated two to three times a weeks for 13 weeks with 940 nm, using LumiPhase™ technology (OPUSMED Inc.). For the sequential pulsing mode, the power density was of $60\mathrm{mW}/{\mathrm{cm}}^2$ for a total fluence of $81\mathrm{J}/{\mathrm{cm}}^2$ (30 min). The pulsing patterns and time on-and-time-off sequences were as follows (see Fig. 1): Pulse duration (time on) $500\mu \mathrm{s}$, pulse interval (time off) $150\mu \mathrm{s}$, 4 pulses per pulse train, and a pulse train interval of $1550\mu \mathrm{s}$. For the CW mode, an irradiance of $60\mathrm{mW}/{\mathrm{cm}}^2$ was used for a total fluence of $81\mathrm{J}/{\mathrm{cm}}^2$ (15 min). The size of the treatment areas were $20\mathrm{cm}\times 10\mathrm{cm}$, and the treatment distance was $4\pm 0.4\mathrm{cm}$.

Fig. 1

Schematization of the sequential pulsing mode used on the left forearm. Pulse duration [time on (PD)] $500\mu \mathrm{s}$, pulse interval [time off (PI)] $150\mu \mathrm{s}$, 4 pulses per pulse train (PPT), and a pulse train interval (PTI) of $1550\mu \mathrm{s}$.

2.2.1.

Digital photographs

Photographs (Canon Dual Flash EOS 10D, Canon, Tokyo, Japan with EX SIGMA 50 mm 1:2.8 macrolens, Sigma, Aizu, Japan) were taken before and at the follow-up visit. Each photograph was taken maintaining as much as possible the identical ambient lighting, pose, and camera angles.

2.2.2.

Skin temperature monitoring

NIR radiation typically induces molecular vibrations and rotations and by so doing increases skin temperature.¹ Papillary dermis temperature was monitored at a depth of 1 and 3 mm with needle probes placed on the interior face of the left forearm throughout the LLLT session (Type-T thermocouple, Omega, Montreal, Canada; Fig. 2).

Fig. 2

Hypodermic needle probe inserted at 1- and 3-mm depth in the dermis during LLLT treatments.

3.

Results

Figure 3 depicts the photographs of the patient’s forearms at baseline and after 13 weeks of LLLT treatment using pulsed or CW delivery mode. Efficacy assessments revealed that both forearms improved after LLLT treatment. However, some differences, mostly in favor of the pulse-treated side, were seen in clinical outcomes.

Fig. 3

Patient forearms before (upper panel) and after (lower panel) LLLT treatments. The left forearm receives LLLT using a sequential pulsing mode and the right forearm receives LLLT using a CW mode.

The percent improvement from baseline was recorded at endpoint for symptoms associated with the patient’s condition. As can be appreciated in Fig. 4, the degree of improvement was greater for most symptoms on the pulse-treated side in comparison to the CW-treated side, with the greatest difference seen for calcium deposits (40% for the pulse side versus 4% for the CW side). A small improvement (5%) was seen in favor of the CW-treated area for strength/ability to lift heavy objects. No difference between treatment sides was observed for ulceration and skin thickness. Symptoms assessment also revealed that only moderate tenderness was noted on both forearms, as documented on the inflammation scale conducted at the end of the treatment period; no swelling or warmth was observed.

Fig. 4

Percent improvement from baseline at endpoint in the degree of symptoms for each forearm.

The clinical assessment was rated at endpoint using a range of responses from 0 (none) through 4 (excellent). The CW-treated forearm was rated as moderately improved, whereas the change seen on the pulse-treated side was deemed excellent. The pattern of results was similar from the patient’s perspective. At the end of the study period, the patient reported being very satisfied with various aspects of both treatments including the ability of the treatment to prevent worsening of symptoms and with the amount of time it took for the treatment to start working; the degree of satisfaction with symptom relief was, however, deemed superior on the pulse-treated side (Q.1 to Q.3). The amount of time necessary to administer the treatment was judged to be somewhat more convenient for the CW-treated forearm in comparison with the pulse-treated forearm (Q.4). The patient also reported no side effects from treatment (Q.5 to Q.8) on either forearm. The patient also judged that the treatment on both forearms was satisfactory outweighing the downside and was overall very satisfied with the treatment (Q.9 to Q.10). The patient stated that she would recommend this treatment to other patients with a similar condition (Q.12). Responses for each forearm on the satisfaction questionnaire are presented in Table 1.

Both the pulse and CW LLLTs were well tolerated. Other than slight erythema noted on the left forearm, no significant treatment-related adverse effects were noted during the entire study period including the presence of discomfort, edema, and pain.

In the present study, skin temperature was monitored. Temperature variations were registered by thermocouple hypodermic probes rigorously placed with adhesive tape and were never greater than 39.8°C at a depth of 1 mm and 38.3°C at 3 mm (typical treatment session temperature curves shown in Fig. 5). Monitoring attested that the skin temperature during LLLT application increased without reaching the skin injury threshold level ($>42°\mathrm{C}$).

Fig. 5

Papillary dermis temperature monitoring with 1- and 3-mm needle probes throughout the LLLT session.

4.

Discussion

Results from this case study suggest that 940-nm LLLT was efficacious in alleviating signs and symptoms associated with lcSSc. Data from the clinical assessment revealed that the LLLT significantly improved the appearance and severity of lesions. Benefits to the patient were also noted from the patient’s perspective. Furthermore, no treatment-emergent adverse effects were observed. Overall, significant functional and morphologic improvements following LLLT treatment were observed with the best results seen with the pulsing mode. One perceived advantage of the CW over the pulse delivery was the treatment duration; however, given the added benefits of the pulsed mode, this does not appear to be a significant drawback.

LLLT therapy appears to bring relief to patients affected by this debilitating disorder in a noninvasive manner. LLLT therapy potentially has two mechanisms of action: thermal and nonthermal. NIR wavelengths can raise skin temperature to 45°C—although the thermal effects do not create tissue injury—so as to provide inside-out heating possibly vasodilating capillaries which in turn increases catabolic processes leading to a reduction of in situ calcinosis.²⁸ Second, nonthermal effects also take place presumably resulting in a cascade of cellular reactions including the modulation of growth factors and inflammatory mediators. It has been suggested that the LLLT anti-inflammatory effects are mediated via the activation of the TGF-$\beta$ complex.^18,19 In this mechanism, LLLT-emitted photons must be absorbed by a molecular chromophore. A growing body of evidence suggests that the photobiomodulation mechanisms are ascribed to the activation of mitochondrial cytochrome c oxidase.²⁹ Respiration in the mitochondria can be inhibited by nitric oxide (NO) binding to cytochrome c oxidase which competitively displaces oxygen and affects cell metabolism. Excess NO binding is associated with inflammatory processes, cell damage, and apoptosis. Light absorption dissociates NO, allowing cellular respiration to resume and normalization of cell activity, ultimately triggering biomolecular processes. Pulsed light delivery, as opposed to a CW mode, might favorably enhance this cellular strategy. Short and intermittent light emissions might enhance NO dissociation, therefore augmenting mitochondrial energy production and cellular activity.

Overall, these preliminary results suggest a beneficial effect on the alleviation and progression of symptoms. While these findings are encouraging, additional research in larger samples of patients is needed to further evaluate this promising therapy. Future studies should include long-term assessments to document maintenance of benefits over time. Further trials are also necessary to identify the cellular processes underlying the mechanisms at play in the therapeutic effect. In the future, LLLT may well become a new treatment option to provide enhanced daily relief to patients with this incapacitating condition. This novel therapeutic modality may broaden the currently restricted therapeutic armamentarium of the disease.