Pain and fatigue in systemic sclerosis: Practical strategies for non-pharmacological management

Abstract

Objective:

Pain and fatigue are among the most prevalent and disabling symptoms in patients with systemic sclerosis, significantly impairing quality of life and daily functioning. Despite their high burden, these symptoms are frequently underrecognized and undertreated by clinicians. This narrative review aims to synthesize current evidence and practical approaches to support multidisciplinary care in the assessment and non-pharmacological management of pain and fatigue in systemic sclerosis.

Methods:

We conducted a comprehensive review of the literature focusing on the multifactorial causes, diagnostic workup, and non-pharmacological treatment strategies for pain and fatigue in systemic sclerosis. This narrative review integrates evidence-based recommendations, expert consensus statements, and reflects best current clinical practice.

Results:

Pain and fatigue in patients with systemic sclerosis are underestimated and often multifactorial. Pain in systemic sclerosis may arise from musculoskeletal, neuropathic, vascular, gastrointestinal, and iatrogenic sources, while fatigue is driven by cardiopulmonary involvement, malnutrition, endocrine dysfunction, poor sleep quality, and psychological factors. Accurate symptom assessment requires a combination of patient-reported outcome measures, clinical examination, imaging modalities, and laboratory testing. Non-pharmacological interventions, including physical rehabilitation, cognitive behavioural therapy, nutritional support, and mind-body practices, demonstrate particularly promising benefits in symptom relief and functional improvement, although high-quality evidence in systemic sclerosis remains limited.

Conclusion:

A personalized, holistic approach is essential to effectively address pain and fatigue in patients with systemic sclerosis. Interdisciplinary care involving rheumatologists, nurses, physiotherapists, nutritionists, psychologists, and occupational therapists is key to optimizing outcomes. Our data show that some unmet needs await to be addressed and therefore an agenda for future research is proposed to improve quality of life in patients with systemic sclerosis.

Introduction

Systemic sclerosis (SSc) is a complex rheumatological disease characterized by interrelated tissue fibrosis, vasculopathy, and immune system dysregulation.^1,2 Great advancements have been made in the systemic (pharmacological) treatment, including internal organ involvements, associated with the disease.^{3 –6} However, among its many systemic manifestations, pain and fatigue are two of the most prevalent and burdensome symptoms, significantly impairing patients’ quality of life (QoL).^7,8 While not life-threatening, their impact on daily functioning is profound, contributing to disability, psychological distress, and reduced social participation. Despite their high prevalence, these symptoms remain frequently underrecognized and undertreated, posing a significant challenge in clinical practice.

Given the various drivers and impact of pain and fatigue in SSc, clinicians must adopt a comprehensive and standardized approach to assess patients and inform the therapeutic strategy. An interdisciplinary approach is essential. Moreover, nurses, whom are often the healthcare professionals that spend the most time with patients, contribute significantly to this process through symptom monitoring, patient education, and the implementation of supportive, non-pharmacological interventions.

The purpose of this narrative review is to provide a focussed synthesis of the relevant literature and practical approaches to specifically guide the management of pain and fatigue in patients with SSc.

Materials and methods

A narrative literature review was conducted searching PubMed database, focusing on English-language articles published from 1 January 2000 to 31 March 2025. Search terms included combinations of ‘systemic sclerosis’, ‘pain’, ‘fatigue’, ‘assessment’, ‘rehabilitation’, ‘non-pharmacological treatment’, ‘nutrition’, ‘psychological therapy’, and ‘quality of life/QoL’. Additional relevant sources (including pre-2000) were also identified through manual search of reference lists and expert consensus documents. Studies were selected for inclusion based on their relevance to clinical practice, including original research, reviews, and international guidelines.

Studies were selected for inclusion based on their clinical relevance and methodological quality, with priority given to peer-reviewed original research, systematic reviews, and international guidelines. No formal risk-of-bias assessment was performed, as this was beyond the scope of a narrative review. In addition to original research and reviews, this work incorporates key international recommendations, including the 2023 EULAR guidelines on SSc treatment and fatigue management, as well as North American and European expert consensus documents on gastrointestinal (GI) and non-pharmacological care.^{3,9 –13}

In selected areas where evidence in SSc was limited, particularly concerning complementary therapies, nutritional interventions, and occupational therapy (OT), supporting data from other autoimmune or rheumatic diseases were also included to illustrate mechanistic plausibility and clinical rationale. This approach was applied selectively and clearly stated within the relevant sections.

Causes of pain and fatigue in SSc

Pain in SSc

Pain is a frequent and debilitating symptom in SSc, ¹⁴ reported in >75% of patients in cross-sectional studies. ⁸ A practical overview of the different types and causes of pain in patients with SSc is presented in Figure 1.

Figure 1.

Different types and causes of pain in SSc.

GERD: gastro-oesophageal reflux disease, SIBO: small intestinal bacterial overgrowth.

Musculoskeletal involvement represents one of the most common sources of pain and discomfort in SSc, affecting between 40% and 80% of patients, with the highest prevalence in those with early diffuse disease. ¹⁵ Different patterns of articular involvement in SSc have been reported, akin to those observed in rheumatoid arthritis (RA), psoriatic arthritis, and osteoarthritis. A distinct SSc-arthropathy has long been suspected, although has yet to be fully elucidated. Tendon involvement is often more apparent rather than overt synovitis, ¹⁵ and erosive disease is rare. Broader hand involvement in SSc, including (but not limited to) joint and tendon contractures, calcinosis, and acro-osteolysis, further exacerbates functional impairment. ¹⁵ Infected digital ulcers (DUs) and calcinosis can be exquisitely painful and requires urgent medical (and sometimes surgical) management (Figure 2).

Figure 2.

Causes of fatigue in SSc.

GERD: gastro-oesophageal reflux syndrome; ILD: interstitial lung disease; PAH: pulmonary arterial hypertension; SIBO: small intestinal bacterial overgrowth.

Fibromyalgia syndrome (FMS) is another significant, yet frequently underdiagnosed, contributor to pain in SSc. This syndrome, distinct from inflammatory pain, manifests as chronic widespread myofascial pain that affects multiple body areas, often accompanied by chronic fatigue and sleep disturbance. While its prevalence in SSc remains uncertain, a post hoc analysis conducted by Malcarne on a previously published dataset ¹⁶ found that 18.6% of 102 SSc patients met the 1990 classification criteria for fibromyalgia, with a predominance in those with early diffuse disease. ¹⁷ This widespread soft tissue tenderness may not only reflect fibromyalgia or central pain sensitization, but also be partially related to disease activity or active skin involvement typical of early diffuse SSc. Higher rates have also been reported in different assembled cohorts (Table 1).

Table 1.

Reported studies of fibromyalgia syndrome (FMS) in SSc.

Authors	Year of publication	Study design	Major findings
Vera-Lastra et al. 18	2017	50 SSc patients, cross-sectional	Depression – 46% FMS – 48% FMS and depression – 28%
Asif et al. 19	2021	Prospective, cross-sectional study	Depression 26.3% FMS – 18.4%
Perrot et al. 20	2017	Included consecutive patients with RA and SSc (n = 122)	FMS by FiRST (screening tool) – 27.8%, by ACR 1990 – 30.3%, by ACR 2010 – 23.7%
El-Rabbat et al. 21	2018	160 patients (50 RA, 50 SLE, 30 SSc)	FMS – 6.67%
Evers et al. 22	2021	147 consecutive patients with SSc	Median pain intensity was 4/10 on an NRS Most frequent major pain localizations were hand and lower back Pain chronification – Stage 1 34.8%, stage 2 45.2%, Stage 3 20.0% Advanced pain chronification significantly more frequent in patients with low back pain
Ayan et al. 23	2022	44 SSc patients with dcSSc	FMS – 62.79%

dcSSc: diffuse cutaneous systemic sclerosis; lcSSc: limited cutaneous SSc; NRS: numeric rating scale; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus.

Neuropathic pain is also relevant to the patient lived experience of pain in SSc, with studies reporting a prevalence ranging from 26.2% to 56.2%.^24,25 Broad-ranging peripheral neuropathic involvements including peripheral neuropathy, small-fibre neuropathy, and nerve compression syndromes, such as carpal tunnel syndrome, can lead to intrusive neurosensory symptoms (e.g. burning sensations, tingling, and heightened pain sensitivity). ²⁶ In a recent cross-sectional observational case–control study, foot peripheral sensorimotor neuropathy was reported in up to 85.3% of patients with SSc, with 80% showing small-fibre and 57% large-fibre involvement (co-existence of both in 51.4%). ²⁷ Furthermore, trigeminal neuropathy has been reported to be more prevalent in SSc compared to the general population. ²⁸

Ischemic pain is a hallmark of peripheral vascular compromise in SSc, particularly in Raynaud’s phenomenon (RP) and ischaemic DUs. Recurrent vasospasm characterizes RP, affects more than 95% of SSc patients,^29,30 and significantly impacts on QoL and hand function.^14,31 Around half of patients may develop painful DUs, which can be extremely painful and challenging to treat.^30,32 Areas of persistent digital pitting (scars) can be associated with significant hand symptoms including overt pain. ³³

Visceral (abdominal) pain is often neglected in descriptions of SSc-related pain. Oesophageal dysmotility and gastroesophageal reflux disease (GERD) are frequent manifestations, potentially leading to retrosternal pain, while small intestinal bacterial overgrowth (SIBO) and altered motility patterns often cause bloating, cramping, and abdominal pain. ¹⁴ These symptoms further compound the burden of disease and contribute to the overall reduction in QoL.

An additional, often overlooked but important potential contributor to painful symptoms in SSc are iatrogenic side effects of prescribed pharmacological treatments. Medications such as mycophenolate mofetil (MMF) and methotrexate (MTX), commonly used for immunosuppression in SSc, can cause significant GI disturbances, including diarrhoea, nausea, vomiting and abdominal cramping, leading to persistent discomfort.^{34 –36} Nintedanib, a tyrosine kinase inhibitor used for the treatment of SSc-associated interstitial lung disease, is also frequently associated with GI side effects including diarrhoea and abdominal pain. ³⁷ Moreover, vasodilators, commonly prescribed to manage RP and DUs, are frequently complicated by adverse effects such as headache, which may further contribute to the overall pain burden in affected patients. ³⁸

Fatigue in SSc

Fatigue, defined as an abnormal and overwhelming sense of tiredness that is disproportionate to activity and not relieved by rest, is one of the most challenging and pervasive symptoms in SSc, and given its diverse and (often overlapping) multifactorial aetiologies it is often difficult to assess and manage. Notably, fatigue rarely presents in isolation, but frequently coexists with other severe symptoms such as breathlessness, often related to cardiopulmonary involvement, GI manifestations, mood disturbances with marked impairment of mental QoL and chronic pain with a substantial impact on physical function. ³⁹

Cardiopulmonary involvement is a major contributor to fatigue in SSc, particularly in patients with SSc-associated interstitial lung disease and pulmonary arterial hypertension. For instance, a cross-sectional study which compared 35 SSc patients with 35 healthy controls demonstrated that reduced diffusion capacity of carbon monoxide, peripheral and respiratory muscle weakness, and dyspnoea severity were significantly associated with higher fatigue scores in SSc patients. ⁴⁰ In addition to pulmonary involvement, cardiac dysfunction, including left ventricular impairment, has been independently linked to severe fatigue in both early and long-standing SSc. ⁴¹ In a previous study, the severity of respiratory involvement (based on the Medsger severity scoring) was negatively correlated with number of steps and time spent lying, and with a trend observed that the severity of cardiac involvement negatively correlated with number of steps, in patients with SSc. ⁴²

Endocrine and metabolic disturbances may play an important role in SSc-associated fatigue. Hypothyroidism, often due to autoimmune thyroiditis, may affect up to 25% of patients, and is known to contribute to fatigue, weight gain, and mood disturbances. ⁴³ A meta-analysis by Elhai et al. ⁴⁴ reported a prevalence of autoimmune thyroid disease in 10.4% of patients with SSc, highlighting a relevant comorbidity that may contribute to fatigue. Vitamin D deficiency, another common finding in SSc, has also been associated with increased fatigue levels, potentially due to its role in musculoskeletal health and immune regulation.^{45 –47} A recent meta-analysis confirmed that patients with SSc have, on average, vitamin D levels 11.68 ng/mL lower than healthy controls, with vitamin D insufficiency (<30 ng/mL) and deficiency (<10 ng/mL) being strongly associated with the disease (odds ratio (OR): 3.58 and 7.67, respectively; both p < 0.001). ⁴⁸ Notably, muscle weakness and atrophy – potential contributors to fatigue – were significantly more frequently observed in patients with vitamin D deficiency compared to those with insufficiency (91.7% vs 55.9%, p = 0.025 and 55.9% vs 8.3%, p = 0.002, respectively). ⁴⁹

Sleep disorders are an underrecognized yet critical factor potentially contributing to fatigue in SSc. Fragmented sleep is common and often driven by dyspnoea, pain, fibromyalgia and nocturnal GERD in SSc.^{50 –52} According to a cross-sectional study by Sariyildiz et al., ⁵³ sleep disturbances – defined as a global Pittsburgh Sleep Quality Index (PSQI) score > 5 – were present in 68.8% of patients with SSc. Compared to healthy controls, SSc patients exhibited significantly worse scores across multiple PSQI domains, including subjective sleep quality, sleep latency, sleep efficiency, sleep disturbances and daytime dysfunction (all p < 0.05). ⁵³ In addition, 62.5% of patients reported depressive symptoms, which showed a strong correlation with impaired sleep quality (r = 0.633, p < 0.001). Fatigue (r = 0.432, p = 0.001), pain (r = 0.543, p < 0.001), GERD (r = 0.310, p = 0.019), dyspnoea (r = 0.258, p = 0.046), and dysphagia (r = 0.290, p = 0.025) were also significantly associated with higher PSQI scores. ⁵³ While obstructive sleep apnoea (OSA) was previously considered rare in this population (presumably to the lower prevalence of obesity in the SSc population), in a cohort study on 38 patients with SSc-ILD, OSA was diagnosed in 58% of cases, with mild, moderate, and severe OSA identified in 34%, 16%, and 8% of patients, respectively. ⁵⁴ These findings highlight the multifactorial origins of poor sleep quality in SSc and its tight interconnection with both somatic symptoms and psychological comorbidities, ultimately exacerbating daytime fatigue and reducing QoL.

GI involvement is a major contributor to fatigue in SSc, given its high prevalence and impact on nutrient absorption and overall metabolic balance. ⁵⁵ Malnutrition and sarcopenia, often secondary to GI involvement, characterized by dysmotility, SIBO, and malabsorption syndromes, are particularly relevant, as they lead to muscle wasting and reduced energy levels. ⁵⁶ Patients with severe GI dysfunction frequently experience unintentional weight loss, chronic diarrhoea, and inadequate nutrient intake, all of which contribute to worsening fatigue. A study from the Australian Scleroderma Cohort demonstrated that low body mass index (BMI) (<18.5 kg/m²), hypoalbuminemia and GI symptoms were all independently associated with more severe fatigue. ⁴¹ While less common in SSc, renal and hepatic involvement likely further exacerbates fatigue when implicated. Renal impairment may cause anaemia and electrolyte imbalances, while liver dysfunction, often secondary to fibrosis, may lead to systemic metabolic disturbances and reduced energy availability.^{57 –59} In an observational, retrospective study by Lorena et al, ⁶⁰ 16.5% of SSc patients showed liver stiffness values consistent with significant fibrosis, and 5.2% exceeded the threshold indicative of cirrhosis.

Psychological factors are strongly associated with fatigue severity in SSc. Depression, anxiety and feelings of hopelessness are prevalent in SSc, and have been shown to be independent predictors of fatigue.^{7,61 –63} A large longitudinal study of 859 patients from the Australian Scleroderma Cohort Study, with a median follow-up of approximately 1–1.3 years between initial and worst-recorded Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores, revealed lower scores on the SF-36 Mental Component Summary (MCS), reflecting worse mental health, were significantly associated with more severe fatigue. ⁴¹ Specifically, in univariable analyses, MCS scores below the cohort median were associated with a 10.1-point decrease in FACIT-F score (95% confidence interval (CI): −12.3 to −7.7; p < 0.01), indicating higher fatigue levels. ⁴¹ Body image dissatisfaction, particularly in patients with extensive skin involvement or DUs, may further contribute to psychological distress and worsen overall fatigue.

Pruritus may also significantly impact interrelated sleep and fatigue, particularly in patients with early diffuse cutaneous SSc.

As previously described, medication side effects, particularly those related to immunosuppressive and antifibrotic therapies, may also contribute to fatigue. It is also worth noting that some medications, such as opioids, while used for pain management, may themselves exacerbate fatigue. A recent longitudinal study on 1981 SSc patients showed that opioid use was associated with greater fatigue burden, possibly reflecting both medication-related adverse effects, such as GI disturbances and respiratory depression, and more severe disease phenotypes. ⁶⁴

Diagnostic workup

Pain assessment

A comprehensive assessment of pain in SSc requires a multimodal approach that integrates patient-reported outcome measures (PROMs), clinical examination and investigation findings including imaging techniques. Given the diverse origins of pain in SSc, accurate differentiation is essential for guiding treatment strategies. A practical algorithm for assessing and managing pain in SSc is summarized in Figure 3.

Figure 3.

Practical algorithm for evaluating and managing pain in SSc.

CBT: cognitive behavioural therapy; GERD: gastro-oesophageal reflux disease; GI: gastrointestinal; MMF: mofetil mycophenolate; MTX: methotrexate; PROMs: patient-reported outcome measures; SIBO: small intestinal bacterial overgrowth.

PROMs are fundamental in evaluating the severity and impact of pain on QoL. The visual analog scale (VAS) remains the most widely used instrument in clinical settings due to its simplicity, while multidimensional tools like the McGill Pain Questionnaire (MPQ) and the Short Form 36 (SF-36) pain subscale provide more comprehensive insights into pain characteristics and its broader functional consequences. ⁶⁵ The PainDetect questionnaire has been validated for identifying neuropathic pain and can help distinguish it from nociceptive pain. ⁶⁶ In addition, GI pain burden may be specifically assessed using validated tools such as the University of California, Los Angeles GI Tract 2.0 (UCLA GIT 2.0) questionnaire and the Patient-Reported Outcomes Measurement Information System 29.0 GI subscales (PROMIS^® 29.0 GI), which provide standardized measures of GI symptom severity and impact on daily life. ⁶⁷

In everyday care, symptom fluctuations related to DUs, RP, and musculoskeletal stiffness are often documented through patient pain diaries, which can be supported and reinforced through regular clinical interactions. Routine assessments by healthcare providers – including nursing staff – often capture subtle changes in pain expression, behaviour, and functional capacity that may not be fully reflected in formal tools. ⁶⁸ These observations can enhance individualized care planning, inform timely reassessment, and support early intervention.

Clinical examination remains key to identifying specific pain sources in SSc. Imaging techniques further aid in characterization. Magnetic resonance imaging (MRI) is preferred for detecting myositis, while musculoskeletal ultrasound (MSUS) is the gold standard for inflammatory joint disease. Nerve conduction studies are useful for diagnosing large-fibre neuropathy, although they are insensitive to small-fibre neuropathy, which requires specialist testing (e.g. quantitative sensory testing).

Fatigue assessment

Similar to pain in SSc, given the multifactorial origin of fatigue in SSc, a comprehensive assessment should be performed to identify underlying contributors. A practical algorithm for assessing and managing fatigue in SSc is summarized in Figure 4.

Figure 4.

Practical algorithm for evaluating and managing fatigue in SSc.

BDI-II: Beck’s Depression Inventory II; BMI: body mass index; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; GERD: gastro-oesophageal reflux disease; GI: gastrointestinal; HADS: hospital anxiety and depression scale; ILD: interstitial lung disease; MMF: mofetil mycophenolate; MTX: methotrexate; MUST: malnutrition universal screening tool; PAH: pulmonary arterial hypertension; PROMs: patient-reported outcome measures; PSQI: Pittsburgh Sleep Quality Index; RA: rheumatoid arthritis; SIBO: small intestinal bacterial overgrowth.

PROMs are, again, the first step in the clinical evaluation phase. The FACIT-F scale and the SF-36 Vitality Subscale are the most used instruments in SSc research and clinical practice. Recent studies have established Minimal Clinically Important Difference values for FACIT-F, where a decline of 3 points signifies worsening fatigue, while a 4-point improvement indicates meaningful symptom relief. ⁶⁹ The Multidimensional Assessment of Fatigue (MAF) is also useful in capturing different fatigue domains, including severity, distress and interference with daily life.^7,70 These measures should be systematically incorporated into routine evaluations to guide treatment decisions and assess response to interventions.

In clinical settings, nurses frequently assist in the administration and interpretation of these tools, and their ongoing patient contact allows for early identification of fatigue-related impairments that may otherwise go unreported.

Cardiopulmonary assessment is a critical component of fatigue evaluation in SSc to exclude significant involvement. Standard endocrine and metabolic workup should include thyroid function tests and serum 25(OH)-vitamin D levels.

The role of sleep disturbances in fatigue has been increasingly recognized, making their evaluation an important aspect of the diagnostic approach. Testing (e.g. polysomography) for OSA should be considered in patients with symptoms of unrefreshing sleep, excessive daytime sleepiness, or witnessed apnoeic episodes. Questionnaires such as the PSQI and Epworth Sleepiness Scale are useful tools for identifying sleep disturbances associated with fatigue Moreover, patient education on sleep hygiene and behavioural strategies is an essential component of fatigue management, helping patients implement practical measures to improve sleep quality and overall QoL. ⁵³

GI and nutritional assessments should not be neglected, as malnutrition, sarcopenia and micronutrient deficiencies are common in SSc patients due to dysmotility and malabsorption. Evaluation may include body composition analysis, serum albumin levels, and nutritional screening to assess for protein-energy malnutrition. ⁹ Thus, preliminary screenings and nutritional education, as well as appropriate referrals to dietitians for a comprehensive dietary evaluation when needed, are essential components of care provided by rheumatologists and nurses who monitor patients’ conditions.

Indeed, biomarkers such as C-reactive protein (CRP), erythrocyte sedimentation rate may offer insights into inflammation-driven fatigue. Elevated CRP and anaemia are independently associated with fatigue severity. ⁴¹

Non-pharmacological management

Given the multifactorial nature of pain and fatigue in SSc, an effective management strategy requires a collaborative, multidisciplinary approach. While pharmacological treatments have been explored, their efficacy remains limited in patients with SSc, particularly for fatigue, with most studies failing to show meaningful improvement.^71,72 As a result, non-pharmacological interventions have gained increasing attention, with recent EULAR and expert consensus recommendations emphasizing their role in the comprehensive care of SSc patients.

Non-pharmacological treatments, including exercise therapy, cognitive behavioural strategies, patient education and rehabilitation programmes, have shown promising benefits for pain reduction and fatigue management in SSc. ¹³ The latest EULAR guidelines highlight physical activity and psychoeducational interventions as the most effective non-pharmacological strategies to address fatigue in inflammatory rheumatic diseases. ¹⁰ However, the supporting evidence in SSc remains limited. In particular, the 2023 EULAR recommendations on fatigue, informed by a systematic review by Parodis et al, ¹³ concluded that there is currently no robust evidence to support any specific non-pharmacological intervention for fatigue in SSc. This highlights the need to extrapolate from related conditions and to strengthen the evidence base in SSc through dedicated studies. Furthermore, a Dutch consensus statement has provided specific recommendations on multidisciplinary care models and rehabilitation approaches aimed at improving pain and fatigue in SSc patients.^11,12 The reader is directed to these comprehensive references for extended expert insights.

The sections below will discuss specific therapeutic approaches to guide the management of pain and fatigue in SSc, integrating the latest recommendations and available evidence, and recognizing that these should be deployed through a combined and holistic approach. Where direct evidence from SSc was unavailable, we explicitly indicated when supporting data were extrapolated from other autoimmune rheumatic diseases, in line with the methodology used by the 2023 EULAR taskforce. ¹³

Lifestyle and physical rehabilitation

A structured rehabilitation approach is essential in SSc to improve physical function, alleviate pain and manage fatigue. Recent guidelines and expert consensus highlight the importance of tailored interventions that address the musculoskeletal, vascular and functional limitations commonly seen in SSc patients. ¹¹ Exercise therapy has emerged as a valuable component of disease management, with both aerobic and resistance training showing benefits in enhancing muscle strength, flexibility and overall functional capacity. ⁷³ Aerobic exercise has been associated with improvements in exercise tolerance and fatigue levels, even in patients with mild ILD. ⁷³ Resistance training, on the other hand, plays a crucial role in preventing muscle atrophy and maintaining joint mobility, particularly in patients at risk of developing tendon and joint contractures. ⁷³ For those with pulmonary involvement, supervised pulmonary rehabilitation programmes have been shown to improve dyspnoea and exercise capacity. ⁷⁴

Physiotherapy and rehabilitation strategies are equally important in addressing joint contractures, stiffness and functional impairment. ⁷⁵ Structured physiotherapy programmes have demonstrated efficacy in improving hand function, grip strength and facial mobility, underscoring the need for early and targeted interventions.^76,77 Stretching exercises focusing on hand and mouth mobility may help prevent contractures and enhance dexterity, ⁷⁸ while hydrotherapy has been reported to provide relief from joint stiffness and pain, particularly in patients with RP and DUs.^79,80 Manual therapy techniques, including lymphatic drainage, may further contribute to reducing skin tightness, improving circulation and preventing fibrosis-related disability. ⁸¹

Nutritional and gut health interventions

Nutritional and gut health interventions are emerging areas of interest in SSc, with potential roles in managing GI dysfunction and possibly modulating systemic inflammation and fatigue, although current evidence remains limited. While no standardized dietary approach exists for SSc, growing evidence supports the role of targeted nutritional strategies in improving patient outcomes.^82,83

Vitamin D supplementation has been investigated for its potential role in mitigating fatigue, particularly in individuals with hypovitaminosis D. ⁴⁵ Studies have suggested that vitamin D may influence fatigue through its effects on inflammatory pathways, neurotransmitter regulation and mitochondrial function. ⁴⁵ Although clinical data specific to SSc remain limited, findings from other autoimmune diseases indicate a possible benefit in reducing fatigue severity with adequate vitamin D supplementation. ⁴⁵ Given the high prevalence of vitamin D deficiency in SSc, routine screening and individualized supplementation should be considered as part of a comprehensive management strategy.

Probiotics and gut microbiome modulation have emerged as possible therapeutic options for patients with GI symptoms, including SIBO and dysmotility. ⁸⁴ The gut microbiota plays a critical role in immune regulation, intestinal permeability and inflammation, all of which are frequently disrupted in SSc. Studies have demonstrated that SSc patients exhibit distinct alterations in microbial composition, with decreased microbial diversity and increased abundance of pro-inflammatory bacteria.^85,86 Probiotic supplementation has been proposed as a means to restore microbial balance and alleviate GI-related symptoms. ⁸⁴ However, further research is needed to determine the optimal strains, dosages and treatment durations for SSc patients.

Dietary modifications aimed at reducing systemic inflammation have also gained attention in SSc. Anti-inflammatory diets, including the ‘Mediterranean’ diet, have been associated with improved fatigue and reduced inflammatory markers in various chronic diseases.^{87 –89} The low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet has been explored in SSc patients with GI symptoms, although its efficacy remains uncertain. ⁸² While some studies report a reduction in gut symptoms and improved QoL, others have found no significant changes in microbial diversity or symptom severity.^83,90 Avoidance of pro-inflammatory foods, such as ultra-processed foods and refined sugars, may help mitigate disease-related inflammation and improve symptoms. ⁸⁸ Any changes to diet and nutrition should follow an individualized assessment, with multidisciplinary input from nurses, dietitians and rheumatologists to ensure safe and effective implementation.

Psychological and behavioural therapies

Psychological and behavioural interventions are fundamental components in the management of pain and fatigue in SSc, addressing the emotional distress and maladaptive coping mechanisms that may exacerbate symptom burden. ⁹¹ Cognitive behavioural therapy (CBT) has shown promise in chronic illnesses and has been preliminarily explored in SSc as a strategy to reduce pain catastrophizing and improve fatigue management. ⁹² CBT interventions focus on reframing negative thoughts, enhancing coping strategies, and promoting behavioural modifications that contribute to improved psychological well-being and physical function. Patients with SSc often struggle with helplessness and maladaptive illness perceptions, which CBT can address, ultimately leading to enhanced self-efficacy and symptom control. ⁹²

Mindfulness-based therapies, such as mindfulness-based stress reduction (MBSR), have also shown promise in improving psychological status and QoL in SSc patients. ⁹³ These interventions promote awareness and acceptance of pain and fatigue, reducing emotional distress and fostering adaptive coping strategies. In a prospective interventional study, 32 SSc patients were enrolled and assigned to either an MBSR group (n = 16) or a waitlist control group (n = 16). ⁹³ The intervention consisted of an 8-week MBSR programme including weekly 2.5- to 3-h sessions, one full-day retreat and daily home practice. While quantitative outcomes such as anxiety, depression, hopelessness, perceived stress and QoL did not show statistically significant improvements, the MBSR group experienced a significant benefit in anger regulation, with significant gains in both internal and external anger control (p = 0.009 and p = 0.045), and reduced overall anger expression (p = 0.014). ⁹³ Qualitative interviews further revealed perceived improvements in emotional awareness, stress reduction, adherence to therapy and reduced fear of disease progression. Patients reported greater ability to accept painful sensations without judgement and to adopt mindfulness in daily life, suggesting enhanced psychological resilience. ⁹³

Another critical aspect of behavioural interventions in SSc is optimizing sleep hygiene, as sleep disturbances are highly prevalent and contribute to both pain and fatigue. ⁹⁴ Nurses and the broader interdisciplinary team can contribute to sleep management by providing patient education on sleep hygiene, assisting in the development of individualized behavioural strategies and supporting adherence to interventions such as maintaining a regular sleep schedule, managing light and noise, and reducing pre-sleep stimulation, to alleviate sleep disturbances and related symptoms in patients with SSc.

OT

OT may significantly contribute to the management of pain, fatigue and disability in SSc, with the aim of preserving functional independence and preventing progressive decline. ⁹⁵ Given the musculoskeletal and vascular involvements characteristic of SSc, OT interventions often include joint protection strategies, adaptive techniques and structured hand rehabilitation programmes (e.g. stretching, splinting, and activity modification), which have been shown to improve dexterity, grip strength and pain-related disability in SSc.^{78,95 –97}

Although most OT interventions in SSc have focused on improving hand function, data from RA suggest that OT can also contribute to fatigue management including through pacing strategies, ergonomic adaptations and energy conservation techniques. ⁹⁸ These approaches may improve daily functioning and endurance, while adaptive devices can support hand efficiency and reduce joint strain. ⁹⁸ Furthermore, OT has been shown to enhance self-efficacy and coping in RA, ⁹⁸ highlighting the potential psychological benefits of a holistic OT approach, although such evidence is currently lacking in SSc and warrants dedicated investigation.

Complementary therapies

Complementary therapies, such as yoga ⁹⁹ and acupuncture ¹⁰⁰ have gained attention as possible adjunctive treatments for SSc, offering potential symptom relief in selected patients. While these approaches do not modify disease progression, they may help improve pain, fatigue and overall well-being, and can be used in combination with systemic (pharmacological) treatment.

By offering guidance on incorporating mind–body practices into self-management routines, rheumatologists and nurses can empower interested patients to make informed choices aligned with their care goals and preferences.

Yoga has increasingly been explored as a complementary therapy in autoimmune diseases for its potential to improve physical and psychological symptoms. In RA, randomized controlled trials (RCTS) and meta-analyses have demonstrated improvements in disease activity, fatigue, pain, and mood following yoga-based interventions, with a recent meta-analysis reporting a standardized mean difference of −0.51 (95% CI −0.71 to −0.30; p < 0.001) in disease activity score 28 (DAS28) scores across three RCTs.^101,102 In other autoimmune diseases such as multiple sclerosis and inflammatory bowel disease, yoga has also been associated with significant improvements in anxiety, depression, self-efficacy and emotional fatigue. ¹⁰³ In SSc, however, evidence remains scarce. To date, only a small case series has reported improvements in VAS pain, stiffness and SF-36 domains following a short residential yoga programme in two female patients. ⁹⁹

Acupuncture has also been investigated for its potential role in managing chronic symptoms such as pain and fatigue in RCTs including over 600 patients found that mind–body interventions, including acupuncture and yoga, were associated with significant improvements in DAS28, with a standardized mean difference of −2.51 (95% CI: −2.89 to −2.14; p < 0.001). ¹⁰¹ In SSc, acupuncture-based techniques have received growing attention for their potential to address symptoms such as GI dysmotility and autonomic imbalance. A small interventional study involving 17 SSc patients demonstrated that transcutaneous electrical nerve stimulation (TENS) applied to GI acupoints significantly reduced upper GI symptoms, improved physical functioning, and restored sympathovagal balance (p = 0.02). ¹⁰⁴ In addition, a focused review identified four original studies reporting potential symptomatic benefit from acupressure and electroacupuncture in SSc, although current data are limited and heterogeneous. ¹⁰⁰

Research gaps and priorities

Despite growing interest and emerging data, pain and fatigue in SSc remain among the least understood and most burdensome symptoms, with limited effective treatments and standardized management strategies. The evidence reviewed in this manuscript highlights several implications for clinical care, education, and research. Table 2 outlines key priorities identified for advancing SSc care concerning pain and fatigue.

Table 2.

Unmet needs and research agenda on approach and management concerning pain and fatigue in SSc.

Research focus	Key questions and future directions in SSc
Pain and fatigue pathobiological mechanisms	What are the specific neuroimmune and vascular mechanisms underlying pain and fatigue?
Fatigue Biomarkers	Can inflammatory markers (e.g. IL-6, TNF-α), metabolic profiles, or gut microbiota signatures predict fatigue severity?
Personalized Management	How can AI-driven models help develop individualized treatment algorithms for pain and fatigue?
Microbiome and GI Health	What is the impact of targeted microbiome modulation (e.g. probiotics, dietary interventions) on fatigue and systemic inflammation?
Exercise and Rehabilitation	What is the safety and the long-term benefits of structured resistance training and pulmonary rehabilitation on fatigue and function?
CBT and Psychological Interventions	Can digital-based CBT and mindfulness therapies improve fatigue outcomes?
Nursing and Multidisciplinary Care	What is the impact of nurse-led symptom monitoring, patient education, and delivery of non-pharmacological interventions on treatment adherence and quality of life?

AI: artificial intelligence; GI: gastrointestinal; CBT: cognitive behavioural therapy.

For clinical practice, our findings support the adoption of personalized, multimodal, and multidisciplinary strategies for assessment and intervention. Non-pharmacological therapies such as physiotherapy, structured exercise programmes, CBT, nutritional optimization, and nurse-led monitoring offer promising options that should be integrated into standard care pathways. Clinicians should be educated to recognize fatigue and pain as potentially modifiable symptoms and proactively screen for contributors such as lung, musculoskeletal or GI involvement, malnutrition, sleep disturbance, and polypharmacy.

There is a need to improve awareness and training among healthcare professionals about evidence-based non-pharmacological strategies. Interprofessional education involving rheumatologists, physiotherapists, dietitians, psychologists, and nurses is essential to deliver truly holistic care.

Areas warranting investigation include (but are not limited to) better understanding of the neuroimmune and vascular pathways underlying fatigue and pain, identification of reliable biomarkers (including cytokines and microbiome-derived signatures), development of AI-driven personalized treatment algorithms, and robust testing of structured rehabilitation programmes and psychological interventions. In particular, the lack of SSc-specific evidence was noted in the recent 2023 EULAR recommendations on fatigue management ¹³ which underscores the urgency of developing SSc-dedicated studies; to reduce symptom burden and improve QoL for people living with SSc.

Conclusion

Despite significant advancements, the significant morbidity from pain and fatigue in SSc remains a frequent and challenging to treat unmet need in the disease. The complex multifactorial aetiology of pain and fatigue in SSc, makes assessment and management particularly complex, and therefore a comprehensive multimodal diagnostic approach is crucial to identifying underlying (and potentially modifiable) contributors. While pharmacological treatments have shown limited efficacy, non-pharmacological interventions, such as exercise therapy, physiotherapy, cognitive behavioural strategies, and gut health modulation, have demonstrated particularly promising benefits. Therefore, a personalized, multidisciplinary approach is essential to support informed patient decision-making. For future research, a broad agenda may be considered but it warrants international collaborative studies to develop the evidence base for various interventions with the aim to improve SSc patients QoL.