Most people with scleroderma develop skin lesions within one year after the onset of Raynaud’s phenomenon (RP), a condition in which the fingers and toes feel numb, prickly, and frigid in response to cold temperatures or stress, a 10-year follow-up study reports.
The findings also showed a continuous increase in the frequency of digital ulcers — small sores on the fingers and toes — during this period.
The study, “Incidence and predictors of cutaneous manifestations during the early course of systemic sclerosis: a 10-year longitudinal study from the EUSTAR database,” was published in the journal Annals of the Rheumatic Disease.
In scleroderma, uncontrolled inflammatory reaction causes hardening or sclerosis of the skin due to the accumulation of collagen. Both skin sclerosis and digital ulcers — sores that form on the toes and fingers due to reduced blood flow — have a significant negative impact on quality of life.
To learn more, researchers at University Hospital Basel, in Switzerland, evaluated when in the disease course these skin manifestations occur, and which factors contribute to earlier presentation.
In total, they analyzed 695 adults (mean age 51.7 years at RP onset) who were part of the European Scleroderma Trials and Research group (EUSTAR) database. Patients had their first visit within one year of onset of Raynaud’s and were followed for 10 years.
Raynaud’s phenomenon, or RP, is characterized by discoloration of the fingers and toes, with reduced sensitivity and associated pain. It is triggered by cold or stress, leading to spasms in small blood vessels and reduced blood flow, and is considered an early sign of scleroderma.
The researchers used the modified Rodnan skin score (mRSS) to assess skin involvement in 17 body parts, including the arms and legs. Skin sclerosis was defined as an mRSS of 2 or higher.
Among the total group of patients, 42% had autoantibodies targeting topoisomerase-I (anti-TOPO), 9.5% had those specific for RNA polymerase-III (anti-RNAP-III), and 16.7% had anticentromere (anti-ACA) autoantibodies. Screening for these autoantibodies —immune proteins that mistakenly target and react with a person’s own tissues or organs — is routine clinical practice for the early diagnosis of scleroderma.
TOPO is a key enzyme for the winding of DNA molecules during gene expression and cell division. It is highly specific to people with scleroderma and linked to diffuse skin disease and lung fibrosis, or scarring.
RNAP-III is a crucial enzyme in the generation of small RNA molecules from DNA. Its autoantibodies are associated with severe disease and diffuse cutaneous involvement — characterized by problems in many organs of the body, especially the lungs and kidneys.
In turn, the centromere is a component of chromosomes and its autoantibodies are typically detected in limited cutaneous scleroderma.
The results showed that the majority of patients developed skin sclerosis in the first year after the onset of RP. The risk for developing the condition in the arms during that 12-month period was higher than developing it in the legs (68.7% vs. 25%).
Patients developed moderate-to-severe skin sclerosis within 6.5 years of RP diagnosis. The likelihood of developing hardened skin during this period was 87.7% in the arms, 23.4% in the chest, 22% in the abdomen, and 41.6% in the legs. Fingers had the highest incidence of skin sclerosis.
The median mRSS peak, 15 points, was reached as early as one year after Raynaud’s onset. Individuals with limited skin involvement reached an mRSS peak of 9.5 points, considerably lower than the median. However, those with diffuse cutaneous disease peaked at a higher value of 23 points.
Researchers estimated that only 1.2% of patients developed a total mRSS higher than 40 points in the first year. In contrast, 24.1% of the people had a mRSS up to 5 in the same period.
Men had an almost two-fold higher risk of reaching an mRSS score of 20 or greater in the first year when compared with women. In addition, individuals older than 52.7 years were more likely to have a similar high score than those younger than this age. However, over five years of follow-up, both groups showed a reduced likelihood of developing severe skin involvement. That risk was approximately 42%.
In addition, 76.4% of those patients positive for anti-RNAP-III autoantibodies developed a mRSS score higher than 20 within the first three years. Those with anti-TOPO autoantibodies also had a higher risk of such score in this period compared with those individuals with anti-centromere antibodies.
Researchers saw a steep increase in the risk of developing digital ulcers in the first year (33.7%). Unlike skin sclerosis, the probability of developing digital ulcers increased continuously during the 10-year follow-up period, to a maximum of 70.2%. Younger patients had a tendency to develop digital ulcers earlier than older individuals, and men were more commonly affected than women.
In contrast with patients with skin sclerosis, those with anti-TOPO antibodies had higher likelihood of developing digital ulcers, while patients with anti-RNAP-III autoantibodies had less risk for this complication.
“By mapping the temporal evolution of skin sclerosis and DUs [digital ulcers] and identifying risk factors early during the disease course, our findings will enable physicians to more accurately counsel patients,” the researchers said.
“The long-term prospective data on the large number of EUSTAR patients presented here will facilitate the design of clinical trials aiming to prevent disease evolution as well as those evaluating new diagnostic tests and therapeutic strategies” they added.