Systemic sclerosis (SSc), also called scleroderma, is a rare chronic autoimmune disease that
can have a wide range of cutaneous, joint, and internal organ involvement. In the skin, SSc
is characterized by enhanced fibroblast activity leading to hypertrophic dermal collagen that
results in thickened, less flexible skin. (Hassani, 2016) SSc is often divided into two types
based on extent of cutaneous involvement: diffuse SSc and limited SSc. The hand is a frequent
area of involvement in both subtypes of SSc. Hand disability in SSc leads to a high burden on
quality of life for patients as it limits both work and activities of daily living. Treatment
for hand sclerosis remains limited with generally progressive disease despite aggressive
treatment with anti-fibrotic medications, immunosuppressive agents, and topical approaches.
Specific hand therapies include physiotherapy and injections of autologous adipose-derived
stromal vascular fraction into the fingers with some success. (Guillaume-Jugnot, 2016; Liem,
2019)
Ultraviolet therapy has been used in dermatology for several decades. UVA-1 is a form of
phototherapy that utilizes the longest wavelengths in the UV spectrum from 340-400 nm. It is
able to penetrate deeper in the skin than other types of phototherapy and target different
types of cells including fibroblasts. In sclerosing skin conditions UVA-1 appears to be
superior to other forms of UV light. Medium to high dose UVA-1 also appears to be superior to
low dose UVA-1 for sclerosing conditions. (Kreuter 2006).
UVA-1 has been reported to be beneficial to skin changes in SSc in several case reports and a
few small studies. (Jacobe 2020) Interpretation of these reports has been difficult based on
the small numbers of subjects involved and the non-blinded non-randomized nature of the
reports. In a single controlled study with half-side comparison of 9 patients, the
investigators could not demonstrate improvement with UVA-1 in the treated hand. (Thomas 2007)
This study was limited by a small number of patients and the long disease duration prior to
treatment (mean of 13 years). A more recent report of a patient with SSc for 2.5 years and
severe acrosclerosis that responded to 21 sessions of UVA-1 with improved mobility and
functionality renews interest in this treatment modality. (Cuenca-Barrales 2019)
If UVA1 therapy can significantly improve hand involvement in SSc with regards to
functionality and disability, it may be a cost-effective and beneficial treatment for this
patient segment with debilitating disease.
Purpose and Objectives:
1. To assess the efficacy of 30 sessions of ultraviolet-1 (UVA1) therapy in treating hand
involvement of SSc in a prospective, randomized, investigator-blinded, intra-patient,
UV-blocking glove-controlled, crossover clinical trial.
1. To compare improvement in hand function as measured by the Hand Mobility in
Scleroderma (HAMIS) test, in the UVA1-treated hand compared to control hand
(gloved).
2. To compare the improvement in hand function as measured by the Cochin hand
functional disability scale (CHFDS) in the UVA1-treated hand compared to control
hand (gloved).
3. To compare the improvement in skin hardening based on durometer measurements in the
UVA1-treated hand compared to control hand (gloved).
4. To measure improvement in the physician measure of skin thickness on hands and
fingers (0-3) scale after completion of 30 UVA1 sessions.
5. To assess the duration of response after a complete 30-treatment course at 3 and12
months post treatment using the HAMIS, CHFDS, durometer, and physician skin
thickness assessment.
2. Assess patient-reported outcomes before, during and after treatment using Skindex-16,
Michigan Hand Questionnaire (MHQ), PROMIS-Physical Function (PROMIS-PF), Hand Disability
in Systemic Sclerosis
- - Digital Ulcers(HDISS-DU) and Visual Analog Scale (VAS).
Study Design:
This study will use a single-blind, prospective, randomized (dominant/non-dominant hand)
comparator design to assess the effect of high dose (80-120 J/cm2) UVA1 therapy on hand
function in scleroderma in a paired t-test design. This study will be placebo-controlled
(with a UV-blocking gloved hand), cross-over, randomized clinical trial. Following the
initial treatment period (30 treatments), patients will have the option to undergo the same
high dose UVA1 treatment protocol on the untreated control hand. A follow up period of 12
months following completion of UVA1 therapy will prospectively follow patients to monitor for
relapse of their disease to assess the durability of the clinical response to UVA1 therapy on
hand scleroderma.
Inclusion criteria:
- - Must be able to understand and provide written informed consent.
- - Scleroderma skin involvement affecting both hands approximately equally.
- - Age of at least 18-years-old.
- - Ability to engage in twice weekly UVA1 sessions.
- - No changes in systemic therapy during the first 100 days of the study period.
Exclusion criteria:
- - On photosensitizing medication.
- - Inability to complete study visits.
- - UV light therapy in the 4 weeks prior to entering the study.
- - Commercial tanning or excessive sun exposure in the 4 weeks prior to entering the study.
- - Current pregnancy or planned pregnancy during the study period.
- - Use of topical therapies other than emollients (suprapotent corticosteroids) in the 2
weeks prior to entering the study.
- - History of intolerance to ultraviolet light.
- - Any other condition that will disqualify the patient from the study in the opinion of
the investigator.
Procedures:
This is a single-blinded, randomized, UV-blocking glove controlled, dominant/non-dominant
hand, cross-over study to determine the efficacy of UVA1 in the treatment of hand
scleroderma. Each participant will have at least one hand treated with UVA1 during the active
treatment period of the study. The study will be performed at the University of Utah
Dermatology Department using both the University of Utah E12 Clinic space as well as the
Midvalley Clinic space. UVA1 lights boxes are located at both E12 and Midvalley locations.
Personnel involved in the study will include the PI, the co-investigators, and the study
coordinators. Approximately 27 patients will be enrolled to account for a 25% drop-out rate.
The number needed to treat to show a difference in the treatment vs.#46; control hands is 21. The
study timeline is summarized in Table 1.
Screening:
For screening, subjects with qualifying scleroderma involving both hands will be asked to
read and sign the informed consent document. They will be reminded that they are to take
their time and, if necessary, take it home for further consideration. Questions will be
answered. Those meeting inclusion / exclusion criteria who have signed informed consent will
be enrolled.
After answering questions and prior to the first treatment the Principal Investigator (PI)
will examine the entire patient and assess for the diagnosis of systemic sclerosis with
bilateral hand involvement and perform the following assessments: HAMIS, CHFDS, durometer
measurements, and mRSS. (Please see efficacy assessment section for details of HAMIS, CHFDS,
durometer, and mRSS). Photographs of the hands and other affected areas will be taken. The
patient will be asked to identify their dominant (writing) hand and their answer will be
noted. Using a random number generator, the patient will be randomized to undergo UVA1
treatment vs.#46;UV-blocking glove (control) on the dominant hand. The non-dominant hand will
receive the other modality. A study coordinator will perform the randomization on the day of
first treatment and the PI will be blinded to the treatment assignment.
UVA1 Treatments:
Blinding:
A UV-blocking glove will be placed on the control hand as determined by the randomization
process. Subjects will wear eyewear that occludes external light.
Evaluations for adverse effects will be carried out by the UVA1 operator (a nurse not
involved in any assessments) and the blinded investigator at prescribed intervals. Evaluation
of UVA1 efficacy on hand scleroderma will be assessed by a trained and experienced evaluator
who is blinded as to the UVA1-treated side (covered / not covered). The efficacy evaluations
will be carried out prior to treatments on days both evaluations and treatments are
completed. After participants have been evaluated at the 3-month post-treatment study visit
the blinded evaluator will become unblinded to the UVA1-treated side for the purpose of
allowing participants to receive standard of care therapy. Therefore, participants will be
allowed to receive additional UVA-1 treatments to one or both hands in addition to any other
necessary standard of care treatments after the 3-month post-treatment visit.
Dosing Schedule:
Prior studies with UVA1 have shown that high and medium dose protocols (>40-120 J/cm2) are
more effective than low dose (20-40 J/cm2) to treat sclerosing skin conditions. (Hassani,
2016) Thus, we will set the initiation dose at 50 J. The hands will be positioned
approximately 9 inches from the bulbs. The palmar surface of the hand will be exposed for
half the treatment and the dorsal surface for half the treatment. If tolerating well after
three treatments, the dose will be increased to 60 J for three treatments and then 70 J for
the remaining treatments.
Patients will return to clinic two-to-three times per week for 30 treatments over a 100-day
period to receive UVA1 treatments. If the patient experiences redness, burning, pain, or
blistering at the treatment site, treatment will be held if active symptoms persist at the
time of the next scheduled treatment. If the symptoms have resolved and the patient has
healed by the next scheduled treatment, the UVA1 energy will be reduced by 10 J of the
previously delivered dose. Dose escalation will then proceed by increasing the UVA1 energy
after three well tolerated treatments.
Evaluations:
1. Efficacy evaluations will be performed at baseline, after 15 UVA1 treatment sessions,
after 30 UVA1 treatment sessions, and at 3 and 12 months after completion of all UVA1
treatments. For each evaluation prior to the 12-month evaluation, one of the
sub-Investigators who is blinded to the treatment assignments will generate and record the
HAMIS, CHFDS, Durometer, and mRSS. Hands will be photographed. Patients will complete all
PROM including using Skindex-16, Michigan Hand Questionnaire (MHQ), PROMIS-Physical Function
(PROMIS-PF), Hand Disability in Systemic Sclerosis
- - Digital Ulcers(HDISS-DU), and Visual
Analog Scale (VAS).
The blinded evaluator will also perform safety evaluation and document study-related adverse
events.
1. Primary Efficacy Measure:
The efficacy will be measured using the HAMIS test score to assess for improvement over
time and as compared to the untreated hand. The primary endpoint will be assessed after
30 UVA1 treatments. The primary endpoint is improvement in HAMIS score as compared to
the untreated hand after 30 UVA1 treatment sessions.
2. Secondary Efficacy Measures:
Secondary efficacy measures include HAMIS test score improvement from baseline in treated and
untreated hands after 30 UVA1 treatment sessions, as well as changes in CHFDS, Durometer
measures, mRSS, Skindex-16, MHQ, PROMIS-PF, and VAS scores between baseline and after 30 UVA1
treatment sessions and (when applicable) between treated and untreated hands. Other secondary
efficacy measures include change in HAMIS test scores CHFDS, Durometer measures, Physician
assessment, Skindex-16, MHQ, PROMIS-PF, HDISS-DU, and VAS scores between completion of 30
UVA1 treatments and 3 and 12 months post-treatment in both hands as compared to baseline and
after 30 UVA1 treatment sessions in each hand. Secondary endpoint measures also include time
to disease worsening after treatment as defined by a 3-point (~10%) increase in HAMIS scores
post-treatment.
Endpoint measure descriptions:
HAMIS is a hand function test developed for adults with systemic sclerosis. HAMIS consists of
9 items designed to measure all movements assessed in an ordinary range of motion
(ROM)-measured hand test. Specific items test finger flexion and extension, thumb abduction,
pincer grip, finger abduction/swelling, dorsal extension and volar extension of the wrist,
and pronation and supination. Each item is graded on a 0-3 scale, where 0 corresponds to
normal function and 3 denotes that the individual is unable to perform the item. Each hand is
assessed separately. The minimum score for HAMIS is 0, representing normal hand function. The
maximum score of HAMIS is 27, representing a high degree of dysfunction. (Sandqvist, 2000)
The CHFDS is a questionnaire with 18 questions concerning daily living activities,
administered by a clinician, which each question scored on a scale from 0 (performed without
difficulty) to 5 (impossible to do). The total score is obtained by adding the scores from
all items (range 0-90), with lower scores indicating normal function and higher scores
indicating poor function. This test was developed for rheumatoid arthritis but has been
validated in scleroderma. (Rannaou, 2007)
A Durometer is an instrument for testing the hardness of various materials. It has been used
in scleroderma to measure the hardness of affected skin as compared to normal skin.
The physician assessment on skin thickness on the hand and fingers based on the modified
Rodnan skin score (mRSS) which is a standard outcome measure for skin disease in systemic
sclerosis. The score is calculated by evaluating the skin thickness at 17 different body
sites. Each site is graded from 0 to 3, with 0 representing normal skin and 3 representing
severe skin thickness. The score is calculated by adding the scores at each site to arrive at
a total score ranging from 0 (normal) to 51 (severe disease). (Khanna, 2017) In this study we
will only calculate the score for the hands and fingers. Total possible score of 6 on each
hand.
Skindex-16 is a 16-item validated assessment for the patient to identify the impact of their
skin disease on three quality of life domains: symptoms, emotions, and physical functioning.
Scores are normalized to a 0-100 scale with 0 representing no impact on quality of life and
100 representing maximal impact.
The Michigan Hand Questionnaire (MHQ) is a 37-item validated instrument exploring
hand-specific outcomes across six domains: overall hand function, activities of daily living
(ADLs), pain, work performance, aesthetics, and patient satisfaction with hand function. It
asks questions separately about each hand, allowing for comparisons between hands. The raw
score is converted to a 0-100 scale. For pain, a higher score indicates more pain, but for
the other five scales, higher scores indicate better hand performance. The score for the
affected hand is obtained by selecting either the right or the left hand score.
Hand Disability in Systemic Sclerosis
- - Digital Ulcers(HDISS-DU) is a patient reported
outcome measure developed to capture the full spectrum of symptoms and disability related to
digital ulcers, which are common and debilitating in scleroderma involving the hands.
The
instrument consists of 24 items. Responses are scored from 1 to 6 (6 scores), where 1 is
'yes, without difficulty', 2 is 'yes, with a little difficulty', 3 is 'yes, with some
difficulty', 4 is 'yes with much difficulty', 5 is 'nearly impossible to do' and 'used
unaffected hand only' (both responses were assigned the same score), and 6 is 'impossible'.
The eighth response option 'did not do this activity in the past 7 days' is scored as
missing. The overall HDISSDU score is calculated as the mean of non-missing item scores (with
a missing data threshold of < 12 items) and ranged from a minimum score of 1 to a maximum
score of 6, with increasing score corresponding to increasing disability.
PROMIS Physical Function (PROMIS-PF) is a computer adaptive test (CAT), wherein initial
screening questions guide the need for additional questions following an iterative algorithm.
For example, if a patient is unable to walk 100 feet without resting, an additional question
about jogging 1 mile would not be asked. A weighted t-score results based on national
averages with 50 as the mean score; >50 means higher physical function, <50 means lower
physical function.
All PROs (Skindex-16, MHQ, PROMIS-PF) will be collected electronically at every visit.
