Impact of innovative treatment using biological drugs for the modulation of diffuse cutaneous systemic sclerosis: A systematic review

Citation: Fernández-Lázaro, D.; Iglesias-Lázaro, M.; Garrosa, E.; Rodríguez-García, S.; Jerves Donoso, D.; Gutiérrez-Abejón, E.; Jorge-Finnigan, C. Impact of Innovative Treatment Using Biological Drugs for the Modulation of Diffuse Cutaneous Systemic Sclerosis: A Systematic Review. Medicina 2023,59, 247. https:// doi.org/10.3390/medicina59020247 Academic Editor: Mauro Salvatore Alessandro Alaibac Received: 20 December 2022 Revised: 19 January 2023 Accepted: 26 January 2023 Published: 27 January 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). medicina Systematic Review Impact of Innovative Treatment Using Biological Drugs for the Modulation of Diffuse Cutaneous Systemic Sclerosis: A Systematic Review Diego Fernández-Lázaro 1,2,* , María Iglesias-Lázaro 1, Evelina Garrosa 2,*, Saray Rodríguez-García3,4, David Jerves Donoso 5,6 , Eduardo Gutiérrez-Abejón7,8 and Conrado Jorge-Finnigan 6,9 1Department of Cellular Biology, Genetics, Histology and Pharmacology, Faculty of Health Sciences, University of Valladolid, Campus of Soria, 42004 Soria, Spain 2Neurobiology Research Group, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain 3Department of Medicine, Faculty of Health Sciences, University of Valladolid, Campus of Soria, 42003 Soria, Spain 4Internal Medicine Department of Soria University Assistance Complex (CAUSO), Santa Bárbara Hospital, Castile and Leon Health (SACyL), 42005 Soria, Spain 5Pneumology Department of Soria University Assistance Complex (CAUSO), Santa Bárbara Hospital, Castile and Leon Health (SACyL), 42003 Soria, Spain 6Department of Anatomy and Radiology, Faculty of Health Sciences, University of Valladolid, Campus of Soria, 42004 Soria, Spain 7 Pharmacological Big Data Laboratory, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain 8Pharmacy Directorate, Castile and Leon Health Council, 47007 Valladolid, Spain 9Dermatology Department of Soria University Assistance Complex (CAUSO), Santa Bárbara Hospital, Castile and Leon Health (SACyL), 42005 Soria, Spain *Correspondence: [email protected] (D.F.-L.); [email protected] (E.G.) Abstract: Scleroderma or systemic sclerosis (SSc) is an autoimmune disease affecting the connective tissue, characterized by fibrosis of the skin and internal organs. There is currently no curative treatment available, so therapeutic action is aimed at a symptomatic treatment of the affected organs. The development of biotechnology has made it possible to implement certain biological drugs that could represent a window of opportunity to modulate the evolution and symptomatology of scleroderma with greater efficacy and less toxicity than conventional treatments. This study aimed to review the current evidence critically and systematically on the effects of biological drugs on the pulmonary function, skin disease, and health status of patients afflicted by diffuse cutaneous systemic sclerosis (dcSSc). Three electronic databases (Pubmed, Dialnet, and Cochrane Library Plus) were systematically searched until the cut-off date of October 2022. The review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and included original articles in English and Spanish with a controlled trial design, comparing biological drug treatments (tocilizumab, belimumab, riociguat, abatacept, and romilkimab) with a control group. The methodological quality of the studies was assessed using the McMaster quantitative form and the PEDro scale. A total of 383 studies were identified, 6 of them met the established criteria and were included in the present systematic review. A total of 426 patients treated with tocilizumab, belimumab, riociguat, abatacept, and romilkimab were included. The results showed substantial non-significant (p< 0.05) improvement trends after treatment with the biological drugs included in this review for the modified Rodnan Scale Value, Forced Vital Capacity, and Carbon Monoxide Diffusion Test; however, no benefits were shown on the Health Assessment Questionnaire–Disability Index when compared to the control group. Biological drugs, therefore, maybe a new therapeutic strategy for dcSSc and could be recommended as an additional and/or adjunctive treatment that promotes anti-fibrotic activity. This review could further define the clinical rationale for the use of biologics in the treatment of dcSSc and could provide key details on the study protocol, design, and outcome reporting. Medicina 2023,59, 247. https://doi.org/10.3390/medicina59020247 https://www.mdpi.com/journal/medicina Medicina 2023,59, 247 2 of 19 Keywords: scleroderma; systemic sclerosis; tocilizumab; belimumab; riociguat; abatacept; pulmonary function; skin disease; health status; safety 1. Introduction Scleroderma refers to a heterogeneous group of autoimmune fibrosing disorders. Etymologically, it is derived from Greek and means “hard skin” (skleros: hard; dermis: skin) [ 1 ]. Scleroderma was first described in 1752 by the Italian physician Carlo Curzio as a disease that “transformed the skin into wood” [ 2 ]. Generalized scleroderma or systemic sclerosis (SSc) is an autoimmune disease that affects the connective tissue, characterized by skin and organ fibrosis (heart, lungs, and kidneys), generalized microvasculopathy, and antibody responses against various cellular antigens and alterations in the immune system [ 3 ]. Clinically, two subtypes can be distinguished: (i) limited cutaneous systemic sclerosis (lcSSc), which progresses slowly by hardening skin in the acral areas, distal to elbows and/or knees, and on the face; (ii) diffuse cutaneous systemic sclerosis (dcSSc) which progresses rapidly by a thickening of the trunk and/or limb proximal regions (Table 1), [ 1 ]. Severe and serious affections occur in some organs (mainly in the lungs, heart, and kidneys), and has a poor prognosis [ 3 ]. In this way, Sulli et al. [ 4 ] demonstrated that blood perfusion is significantly lower in patients with SSc than in healthy subjects. The most affected parts were the fingertips, periungual, and palm areas, but not on the face or back of the hands, highlighting a selective affectation of the microcirculation due to the damage caused by SSc. These investigators used laser speckle contrast analysis (LASCA), which was an innovative safe technique to quantify blood perfusion (BP) in different areas of the body [4]. Table 1. Clinical signs, prevalence, and symptomatology in diffuse cutaneous systemic sclerosis (dcSSc). Involved Organ(s) Clinical Signs Prevalence Symptomatology Vascular [4,5] Raynaud’s phenomenon 100% Changes in skin coloration Digital ulcers 41.6% Hard-to-heal lesions → infection, osteomyelitis, gangrene Cutaneous [6] Dermal hardening 100% Pigmentation alterations Patchy areas of depigmentation. Calcinosis cutis Subcutaneous nodules Pain Musculoskeletal [5]Fibrosis 46–97% Contractures Morning stiffness Arthritis Arthralgias Gastrointestinal [7] Esophageal hypomotility 90% Dysphagia Gastroesophageal reflux Bacterial overgrowth Stomach hypomotility Delayed emptying → Premature satiety, fullness, bloating, nausea Intestinal hypomotility Chronic intestinal pseudo-obstruction Malabsorption Anorectal dysfunction Incontinence Medicina 2023,59, 247 3 of 19 Table 1. Cont. Involved Organ(s) Clinical Signs Prevalence Symptomatology Renal [8] Renal scleroderma crisis 10% Malignant high blood pressure Angiopathic hemolytic anemia Thrombocytopenia Proteinuria Macrohematuria Acute renal failure Cardiac [9] Arrhythmias Ventricular 90% Fatigue Palpitations Syncope Dizziness Supraventricular 66% Ventricular multiform premature beats 40% Left bundle branch block 16% First-degree atrioventricular blocks 8% Pericardial conditions Pericardial effusion 78% Chest pain Dyspnea Fever Pericarditis 77.5% Myocardial dysfunction RV dysfunction 69% Fatigue Calf edema Dyspnea Venous congestion LV dysfunction 46% Cardiac failure 20–25% Valvular dysfunction Mitral valves prolapse 20% Dyspnea Pain Edema Palpitations Fatigue Pulmonary [2] Pulmonary interstitial disease 40% Dyspnea Dry cough Crackles Pulmonary arterial hypertension Cor pulmonale Pulmonary arterial hypertension 15–20% RV hypertrophy ↓Cardiac output Heart failure Abbreviations: RV: right ventricle; LV: left ventricle; ↓: decrease; →: produces. Currently, the annual incidence is 1 to 20 cases per million per year [ 10 ], with variations found depending on the geographical area, which may suggest that the rate of occurrence of new cases in the susceptible, at-risk population is conditioned by a genetic predisposition, individual hormonal behavioral determinants, and exposure to environmental factors [ 10 – 12 ]. The incidence is higher in the United States than in Europe, with a higher prevalence in African Americans than Caucasians [ 5 ]. SSc is more common in women than men, at a ratio of 3–5 women to every man, with the highest incidence rates between the ages of 30 and 50 years [ 5 ]. No gender differences were observed in vascular or gastrointestinal involvement; however, tendon rubbing or forced vital capacity (FVC) <70% occurs more commonly in men than in women. Regarding the age of mortality, it does not differ significantly between the sexes. Notwithstanding, for the male group, the development of symptoms and mortality is higher [ 12 ]. A positive correlation has been observed between different major histocompatibility complex (MHC) class II haplotypes and certain antibody subtypes (anti-centromere antibodies (ACA), HLA-DQB1*0501 and anti-topoisomerase) rarely found in healthy people or other connective tissue diseases [ 13 , 14 ]. Similarly, several alleles (HLA-DRB1*1501, DRB1*0701, DQA1*0102, DQB1*0602) have been described that Medicina 2023,59, 247 4 of 19 could have a protective effect against SSc, as they have been found to be decreased in patients with the disease. The same polymorphism in the PTPN22 gene, associated with other autoimmune diseases, is also linked to SSc [ 15 ]. Exposure to silica, vinyl chloride, resins, and organic solvents and infections, cytomegalovirus, and parvovirus B19 are all known to trigger SSc in susceptible individuals [5]. The preliminary classificatory criteria for the classification of SSc were developed in 1980 by the American College of Rheumatology (ACR); advances in diagnostic tools and a joint effort by the ACR and the European League Against Rheumatism (EULAR) in 2013 allowed them to be expanded, giving them greater sensitivity and specificity, by including patients with early disease or very limited skin involvement (Table 2) [ 16 ]. In relation to laboratory findings, more than 95% of patients with SSc develop positive antinuclear antibodies (ANA), with ACA and anti-polymerase I being the most frequent, although up to seven specific ANA have been described; with anti-Scl70, anti-Th/To, and anti- U3RNP being those associated with a worse patient prognosis [ 17 ]. Other complementary tests include: radiodiagnostics for the detection of calcinosis; respiratory function tests assessing (FVC and carbon monoxide diffusion test (DLCO)); Doppler echocardiograms, electrocardiograms, and a Holter monitor for the study of cardiac involvement; barium esophageal study, esophageal manometries, breath tests and digestive endoscopies for digestive tract involvement; in addition, arterial monitoring and a Doppler ultrasound are used to assess renal involvement [18,19]. Table 2. ACR/EULAR 2013 Systemic Scleroderma classification criteria. Adapted from Van Den Hoogen et al. [16]. Items Sub-Item(s) Weight/Score Skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal joints (sufficient criterion) 9 Skin thickening of the fingers (only count the higher score) Puffy fingers 2 Sclerodactyly of the fingers (distal to the metacarpophalangeal joints but proximal to the interphalangeal joints) 4 Fingertip lesions (only count the higher score) Digital tip ulcers 2 Fingertip pitting scars 3 Telangiectasia 2 Abnormal nailfold capillaries 2 Pulmonary arterial hypertension and/or interstitial lung disease (maximum score is 2) Pulmonary arterial hypertension 2 Interstitial lung disease 2 Raynaud’s phenomenon 2 SSc-related autoantibodies (anticentromere, anti-topoisomerase I [anti–Scl-70], anti-RNA polymerase III) (maximum score is 3) Anticentromere 3 Anti–topoisomerase I 3 Anti–RNA polymerase III 3 Abbreviations: SSc: systemic sclerosis. These criteria are applicable to any patient considered for inclusion in an SSc study. The criteria are not applicable to patients with skin thickenings paring the fingers or to patients who have a scleroderma-like disorder that better explains their manifestations (e.g., nephrogenic sclerosing fibrosis, generalized morphea, eosinophilic fasciitis, scleredema diabeticorum, scleromyxedema, erythromyalgia, porphyria, lichen sclerosis, graft-versus-host disease, diabetic cheerio arthropathy). The total score is determined by adding the maximum weight (score) in each category. Patients with a total score of 9 are classified as having definite SSc. There is currently no curative or disease-modifying treatment available. Moreover, the loss of efficacy over time over long periods of treatment and with significant side effects has been demonstrated. Thus, therapeutic action will be aimed at symptomatic treatments of the affected organs according to their severity, depending on the evolution Medicina 2023,59, 247 5 of 19 and duration of the disease [ 20 ]. Therefore, the need for an individualized precision pharmacological regimen seems obvious. To this end, therapeutic algorithms have been developed that provide for general measures such as first-, second-, and third-line drug regimens (Table 3) [ 20 , 21 ]. The Janus kinase (JAK) signaling pathway is an area of emerging interest in dermatology. In fact, recently, Moriana et al. [ 22 ] reported that JAK inhibitors could represent a safe and effective treatment option for cutaneous fibrosis and interstitial lung disease (ILD) in SSc. Additionally, the combination of two immunosuppressants, rituximab plus methotrexate, had potential efficacy for the skin and stabilization of internal organ involvement, and on some microangiopathies in early dcSSc [ 3 ]. In recent decades, the development of biotechnology has made it possible to implement hundreds of biological drugs, which are large protein molecules produced by living organisms that modulate the course of a disease by acting on a specific target. Biological drugs include hormones, monoclonal antibodies, blood products, immunomodulators, and vaccines [ 23 ]. According to the European Medicines Agency (EMA), a biosimilar is a biological drug that contains a version of the active substance of an original biological product or reference product whose patent has expired [ 24 ]. Biological drugs may represent a window of opportunity to modulate the progression and symptomatology of SSc with greater efficacy and lower toxicity than conventional treatments [ 20 ] (Table 4). Therefore, the purpose of this study was to review the current evidence critically and systematically on the effects of biological drugs on the health biomarkers of patients afflicted by dcSSc. The review protocol is published in the Prospective Registry of Systematic Reviews (PROSPERO); reference CRD42023387373. Medicina 2023,59, 247 6 of 19 Table 3. Therapeutic strategies used in the treatment of systemic sclerosis (SSc). Affectation General Measures 1st Line Treatment 2nd Line Treatment 3rd Line Treatment New Therapeutic Tools Peripheral vascular [4,5] Avoid exposure to cold, sudden changes in temperature, stress, smoking, vasospastic substances. Calcium channel blockers Phosphodiesterase-5 inhibitors If severe RP: Prostanoids Prostacyclins and prostaglandins (Iloprost, Treprostanil) Statins Topical agents Biologic drugs (Riociguat, Bosentan) Botulinum toxin If mild RP: Calcium channel blockers or angiotensin receptor blockers. Skin involvement Skin [5] mRSS ≤32 Avoid friction and trauma Methotrexate Mycophenolate mofetil Pirfenidone Nintendanib Rituximab mRSS > 32 Mycophenolate mofetil Methotrexate Cyclophosphamides Hematopoietic cell transplantation Pirfenidone Nintendanib Rituximab DU prevention Calcium channel blockers Phosphodiesterase-5 inhibitors Bosentan Prostaglandins DU treatment Calcium channel blockers Phosphodiesterase-5 inhibitors Prostanoids Musculoskeletal [5]Moderate exercise and physiotherapy Methotrexate Low dose Corticosteroid Hydroxychloroquines Rituximab Tocilizumab Abatacept Gastrointestinal [7] ↓Motility Prevent malnutrition Proton pump inhibitors Agents that high motility Surgical treatment Bacterial overgrowth Antibiotherapy Renal [25] Angiotensinconverting enzyme inhibitors Calcium channel blockers Aldosterone II receptor antagonists Renal replacement therapy Dialysis Medicina 2023,59, 247 7 of 19 Table 3. Cont. Affectation General Measures 1st Line Treatment 2nd Line Treatment 3rd Line Treatment New Therapeutic Tools Renal Crisis [25] Renal replacement therapy Dialysis Cardiac [9] Arrhythmias Verapamil Amiodarone Ablation Pacemaker Pericardial involvement Anti-inflammatory drugs Corticosteroids Pericardial drainage Pericardiocentesis Myocardial dysfunction Angiotensinconverting enzyme inhibitors Beta-blockers Diuretics Cardiac resynchronization Valvular dysfunction Cardiac transplantation Transplantation of affected valves Pulmonary [2]Mycophenolate mofetil Lung transplantation Rituximab Tocilizumab Abbreviations: RP: Raynaud’s phenomenon; MmRSS: modified Rodnan scale; DU: digital ulcers. Table 4. Function and mechanism of the biological drugs used for the treatment of systemic sclerosis (SSc) included in this systematic review. Drug Function Mechanism Tocilizumab Immunosuppressant It binds to soluble and membrane-bound IL-6 receptors and inhibits IL-6-mediated signaling Belimumab Selective immunosuppressant IgG1 monoclonal antibody that specifically binds to the soluble form of human B-cell-stimulating protein Riociguat Anti-hypertension pulmonary Stimulator of the soluble guanylyl cyclase Abatacept Selective immunosuppressant Selectively modulates a key co-stimulatory signal for the full activation of T lymphocytes expressing CD28 Romilkimab Selective immunosuppressant Biospecific antibody to IgG4 which neutralizes IL-4 and IL-13 Abbreviations: IgG: immunoglobulin G; IL: interleukin. Medicina 2023,59, 247 8 of 19 2. Materials and Methods 2.1. Search Strategy This systematic review was conducted following the specific methodological guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) [ 26 ] and the PICO question model for the definition of the inclusion criteria: P (population): “dcSSc’s patients”; I (intervention): “treatment with biological drugs”; C (comparison): “same conditions with placebo, sham therapy or no intervention or pre/post comparison data group”; O (outcomes): “Skin disease (modified Rodnan scale value [mRSS]); pulmonary function test (forced vital capacity [FVC] and carbon monoxide diffusing capacity [DLCO]); and health status (Health Assessment Questionnaire [HAQ] Disability Index [DI] → HAQ-DI Scale). These parameters were included as outcomes as they are commonly investigated in health biomarker studies and in SSc research [27]. A structured search was carried out in the electronic databases: Medline (PubMed), Dialnet, and Cochrane Library Plus between September 2022 and December 2022. Publications from the last 5 years were included, given the evolution of the research in biological treatments for autoimmune diseases. Search terms included a mix of medical subject headings (MeSH) and free text words for key concepts related to biological drugs and SSc: scleroderma, systemic sclerosis, scleroderma diffuse, diffuse cutaneous systemic sclerosis, therapeutics, tocilizumab, biological therapy, antibodies, and monoclonal (monoclonal antibodies); all linked using the Boolean operators OR and AND. The complete search strategy is included in Appendix A. The review was carried out completely independently —titles, abstracts, and full texts—by two investigators (D.F.-L. and M.I.-L.). In addition, the inclusion criteria were independently evaluated and the disagreements generated were resolved by another reviewer (C.J-F.). There were no additional records of reference lists of the relevant articles or gray literature. 2.2. Inclusion and Exclusion Criteria To select the studies, the following inclusion criteria were applied: (i) adults with the condition dcSSc; (ii) studies evaluating the effect of biological drugs accepted for the treatment of dcSSc in humans (excluding animal and/or in vitro studies); (iii) clinical trials, randomized and non-randomized trials, and pre-test/post-test designed studies (excluding reviews, notes, and other-than-original studies); (iv) studies evaluating outcomes (primary or secondary) of skin, respiratory, and functional capacity biomarkers; (v) studies that clearly report the dose, frequency, and route of drug administration; (vi) languages were restricted to English and Spanish; (vii) articles of methodological quality ≥ 11 points according to the McMaster University Occupational Therapy Evidence-Based Practice Research Group for quantitative studies [ 28 ] and ≥ 9 points according to the Physiotherapy Evidence Database (PEDro) scale [ 29 ]. Records that did not meet the criteria were excluded from this systematic review. 2.3. Methodological Quality Assessment The methodological quality of the articles was assessed using the McMaster University Occupational Therapy Evidence-Based Practice Research Group [ 28 ] and the PEDro scale [29] as tools designed to assess the methodological quality of clinical designs. 2.4. Data Extraction The data of the selected studies were summarized in Table 5. The following information was included: name of the first author, year of publication, country where the study was conducted, study design, sample size, gender and age of the participants, duration of the intervention, dose, and mode of administration of the treatment. This was performed by two study investigators (D.F.-L. and M.I.-L.) and disagreements were resolved by the intervention of another study investigator (C.J.-F.). Medicina 2023,59, 247 9 of 19 Table 5. Studies included in the systematic review of the effect of biological drugs on health biomarkers in patients afflicted by diffuse cutaneous systemic sclerosis. First Author, Year of Publication, Country, and Drug Study Design Participants (Baseline Sample Size, Age, Sex, Withdrawals, and Final Group Sample Size) Intervention Outcomes Results Allanore et al., 2020 France [30] Romilkimab Phase II, randomized, double-blind, placebo-controlled clinical study 20 ♂and 77 ♀ >18 years Study withdrawals: 10 no= 48 Romilkimab no= 49 PBO 200 mg Romilkimab or PBO SC/week for 24 weeks. mRSS FVC% DLCO% HAQ-DI GI vs. GC: ↓* mRSS ↑FVC % ↑DLCO % ↓HAQ-DI score Changes from baseline: ↓* mRSS ↓FVC % ↓DLCO % ↓HAQ-DI score Gordon et al., 2018 USA [31] Belimumab Randomized, double-blind, placebo-controlled pilot study n= 20 >18 years Study withdrawals: 2 no= 7 Belimumab + MMF no= 10 PBO + MMF n= 6 Belimumab + MMF n= 9 PBO + MMF 10 mg/kg Belimumab or PBO c/2 weeks first 3 doses and c/4 weeks until week 48 + 1000 mg 2 times/day MMF 48 weeks mRSS FCV% DLCO% GI vs. GC: ↓mRSS ↑FVC % ↑DLCO % Changes from baseline: ↓* mRSS ↑* FVC % ↑* DLCO % Khanna et al., 2018 USA [32] Tocilizumab Phase II, randomized, double-blind, placebo-controlled clinical trial 20 ♂and 67 ♀ >18 years Study withdrawals: 36 no= 44 PBO no= 43 TCZ no= 31 PBO-TCZ no= 30 TCZ-TCZ n= 24 PBO-TCZ n= 27 TCZ-TCZ 162 mg TCZ sc 48 weeks double blind + 162 mg TCZ sc 48 weeks open period total Mrss HAQ-DI score FCV% DLCO % GI vs. GC: ↓total mRSS ↔HAQ-DI score ↓FVC% ↓DLCO % Changes from baseline: ↓total mRSS ↓HAQ-DI score ↓FVC % ↓DLCO % Medicina 2023,59, 247 16 of 19 4.6. Strengths and Limitations The authors of this review acknowledge some limitations. First, a limited number of manuscripts met the inclusion criteria. Nevertheless, our systematic approach followed the PRISMA method [ 26 ] and the search was conducted using three electronic databases (Pubmed, Dialnet, and Cochrane Library Plus). The McMaster methodological quality assessment tool [ 28 ] and the PEDro scale [ 29 ] were used to ensure that all selected records met the minimum quality criteria, and a number of outcomes commonly used in chronic disease drug research were included. Further, our systematic review was registered in the PROSPERO (CRD42023387373) public database. Secondly, there is a large heterogeneity of studies in terms of outcomes, dosage of supplements, and duration of intervention that justifies caution in interpreting the results. 5. Conclusions Biological drugs have the potential to provide a therapeutic alternative as an add-on and/or adjunctive treatment to biological drugs with anti-fibrotic activity. Considering the results included in this systematic review (MRSS, FVC, DLCO), biologics would potentially improve tissue function, highly correlated with survival, although no benefits over HAQ-DI have been reported, or severity of adverse effects. This review could further define the clinical rationale for the use of biologics in the treatment of dcSSc and could provide key details on the study protocol, design, and outcome reporting. However, further studies on the treatment of dcSSc with biologics are required. Author Contributions: D.F.-L.: conceived and designed the research, analyzed, and interpreted the data, drafted the paper, and approved the final version submitted for publication; M.I.-L., E.G. and C.J.-F.: analyzed and interpreted the data and critically reviewed the paper; S.R.-G., D.J.D. and E.G.-A. prepared figures and/or tables and approved the final draft. All authors have read and agreed to the published version of the manuscript. Funding: This research has been funded by (i) Chair of Knowledge and Innovation “Caja Rural de Soria” (Spain) in the call for funding of research projects related to the completion of end-of-degree projects 2022, with project number SO-12-2022. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Acknowledgments: The authors want to thank: (i) Neurobiology Research Group, Department of Cellular Biology, Genetics, Histology and Pharmacology, Faculty of Medicine, University of Valladolid, for their collaboration on infrastructure computer support; and (ii) Blanca García Gómez, Director of the Chair of Knowledge and Innovation “Caja Rural de Soria” (Spain) for their support and involvement in this study. Conflicts of Interest: The authors declare no conflict of interest. Appendix A. Search Sequence Followed for Selection of Articles #1 “Scleroderma, systemic sclerosis” [Mesh] #2 “Scleroderma diffuse, diffuse cutaneous systemic sclerosis” [Mesh] #3 #1 OR #2 #4 “Therapeutics” [Mesh] OR “Tocilizumab” [Mesh] OR “Biological Therapy” [Mesh] OR “Antibodies, monoclonal” [Mesh] OR “Antibodies, monoclonal” [Mesh]. #5 #3 AND #4 The search was conducted in the following electronic databases: Medline (PubMed), Dialnet, and Cochrane Library Plus between September 2022 and December 2022. Languages were restricted to English and Spanish. Medicina 2023,59, 247 17 of 19 Table A1. Results of the methodological quality assessment of included studies—McMaster Critical Review Form for Quantitative Studies [28]. Study Item Total % Quality Score 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Allanore et al. (2020) [30] 1111111111111111 16 100 E Gordon et al. (2018) [31] 1111111100001011 11 68.7 G Khanna Dinesh et al. (2018) [32]1111111100111111 14 87.5 VG Khanna et al. (2020) [33] 1111111111011111 15 93.7 E Khanna et al. (2020) [34] 1111111111011111 15 93.7 E Shima et al. (2019) [35] 1111111111111101 15 93.7 E Abbreviations: 0 = not fulfilled criterion; 1 = fulfilled criterion; E = excellent; VG = very good; G = good. Item 1: study purpose; item 2: literature review; item 3: study design; item 4: blinding; item 5: sample description; item 6: sample size; item 7: ethics and consent; item 8: validity of outcomes; item 9: reliability of outcomes; item 10: intervention description; item 11: statistical significance; item 12: statistical analysis; item 13: clinical importance; item 14: conclusions; item 15: clinical implications; and item 16: study limitations. Table A2. Results of the methodological quality assessment of included studies—PEDro scale [29]. Study Item Total % Quality Score 1 2 3 4 5 6 7 8 9 10 11 Allanore et al. (2020) [30] 11 100 E Gordon et al. (2018) [31] 11 100 E Khanna Dinesh et al. (2018) [32]10 90.9 VG Khanna et al. (2020) [33] 10 90.9 VG Khanna et al. (2020) [34] 11 100 E Shima et al. (2019) [35] 11 100 E Abbreviations: Red = not fulfilled criterion; Green = fulfilled criterion; E = excellent; VG = very good; G = good; F = fair. References 1. Fett, N. 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