Systemic sclerosis induced by CNS stimulants for ADHD: A case series and review of the literature

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Abstract

Introduction

Methylphenidate (Ritalin) is a CNS stimulant, and is a common treatment for children and adults with ADHD. It has been associated with Raynaud's phenomenon (RP) but not with Systemic Sclerosis (SSc). We report a case series of patients pointing out the connection between Methylphenidate and SSc.

Cases

We identified three patients in a single Rheumatology clinic in Israel, who developed SSc following treatment with CNS stimulants for ADHD. All three cases had Raynaud's phenomenon, skin changes, pathological capillaroscopy and positive ANA. Symptoms appeared and worsened over months following the use of methylphenidate and subsided after its cessation.

Conclusion

This is the first report in the literature of a causative relation between methylphenidate and the development of SSc, a serious, life-threatening condition. Patients treated with CNS stimulants should be followed closely for side-effects such as RP and skin changes.

Introduction

Raynaud's phenomenon (RP) is a clinical syndrome characterized by recurrent episodes of vasospasm involving peripheral small vessels, triggered by exposure to physical, chemical or emotional stress [1]. RP is very common in young adults with a prevalence of 3–5% in the general population [2,3]. Abnormalities of the blood vessel wall, of neural control mechanisms and of circulating factors are known to interact in the pathogenesis of RP [2].

RP is often referred to as primary or secondary depending on whether it occurs as an isolated condition with no associated cause (primary RP) or is associated with an underlying condition (mainly connective tissue diseases), or other causes of vasospasm in the blood vessels (secondary RP) [4].

Some drugs and toxic substances with a vasoconstrictor effect are associated with the development of RP [1,4,5]. Drug-induced RP is attributed mainly to chemotherapy drugs, cyclosporin, estrogens, sympathetic mimetic agents, non-selective beta blockers, etc.

Cases of RP induced by central nervous system (CNS) stimulants have been reported [[5], [6], [7], [8], [9], [10]]. Medications used to treat attention deficit hyperactivity disorder (ADHD) cause central stimulation of the dopaminergic and noradrenergic system which is responsible for the peripheral release of catecholamines leading to vasoconstriction [5]. The largest study that investigated whether these ADHD medications were associated with the development of RP, was a retrospective case-control study by Goldman et al. in 2008 [7]. The authors enrolled 32 children with RP and compared them to a group of 32 matched controls without RP. A significant association between the presence of RP and past or current use of ADHD stimulants was found.

A retrospective chart review by Coulombe et al. identified high incidence of exposure to ADHD stimulants among children diagnosed with abnormal sensitivity to cold, but the rates of RP specifically were low and similar between groups [11]. None of the patients in these series and case reports was subsequently diagnosed with a connective tissue disease.

Systemic sclerosis (SSc) is a chronic connective tissue disease (CTD) characterized by inflammation and fibrosis of the skin, vascular abnormalities, visceral damage, and production of autoantibodies [12]. SSc is the CTD most frequently associated with RP (96%) [[13], [14], [15]], which is often the first clinical manifestation of SSc.

Some case reports about drug-induced SSc have been published [[16], [17], [18]] but none was secondary to the use of CNS stimulants to treat ADHD. Cocaine, an addictive stimulant, has been implicated in SSc and scleroderma-like disorders [19]. In reports of drug-induced sclerodermiform diseases, the lack of RP, capillaroscopic abnormalities or scleroderma-specific autoantibodies helped differentiate these conditions from SSc [20].

We describe a case series of 3 patients followed in a rheumatology clinic in a single center in Israel, that were diagnosed with SSc following treatment with CNS stimulants.

Section snippets

Cases

The first patient is a 41-year-old-female. She has had RP since around the age of 12 years. She was first prescribed methylphenidate (the most common CNS stimulant for ADHD) during her university studies, and at the age of 23 years, started taking the instant release formulation (Ritalin). Six months later, her RP worsened but she had no ulcers or skin changes. At the age of 26 years, she began adding the extended release form of methylphenidate (Concerta) intermittently and at the age of 37,

Discussion

ADHD affects around 3% to 4% of children and adolescents [21] and often continues into adulthood [22,23]. Methylphenidate, a CNS stimulant, is the first-line and most common pharmacological treatment for ADHD [24]. Known adverse events include decreased appetite, growth retardation and sleep disturbance, although most are transient [25].

CNS stimulants are sympathomimetics that cause vasoconstriction and have been associated with RP [[5], [6], [7], [8], [9], [10]]. A review of literature did not

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

None.

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