Open access peer-reviewed chapter

Survival, Mortality, Causes of Death and Risk Factors of Poor Outcome

Written By

Manuel Rubio-Rivas

Submitted: May 17th, 2016 Reviewed: March 14th, 2017 Published: October 4th, 2017

DOI: 10.5772/intechopen.68549

Chapter metrics overview

1,192 Chapter Downloads

View Full Metrics

Abstract

Systemic sclerosis is a rare autoimmune disorder with a historically bad prognosis. Survival has been improving over time and we can currently estimate a 1-year survival, 94.9; a 5-year survival, 84.4; a 10-year survival, 70.9 and a 20-year survival, 44.9%, from the time of diagnosis. Accordingly, mortality has been decreasing over time, being the overall standardized mortality ratio (SMR) 2.72 (1.90–3.83), SMR 2.4 after 1990. Among the SSc-related causes of death, the lung death is the most important cause and its relative percentage is increasing over time since the introduction of ACE inhibitors for the treatment of scleroderma renal crisis (SRC) in early 1990s. Among the SSc-non-related causes of death, cancer, infection and cardiovascular disorders are the leading causes of death. Risk factor predictors of poor outcomes are an elder age at diagnosis, the male gender, diffuse subset, visceral involvement and non-Raynaud’s phenomenon onset.

Keywords

  • systemic sclerosis
  • survival
  • mortality
  • death
  • prognosis

1. Introduction

Systemic sclerosis (SSc) represents one of the autoimmune systemic diseases with worse prognosis. It was actually a devastating scenario until it became well advanced in the twentieth century in terms of survival and mortality, but since late 1980s, the knowledge and course of scleroderma have been progressively improving. Nowadays, more risk factors are recognized and allow physicians to focus on patients with worse prognosis. As traditional SSc-related involvements improved, secondary involvements or SSc-non-related diseases have gained prominence.

Advertisement

2. Survival

Scleroderma was a devastating disease for ages. Physicians were short of proper tools to change significantly the prognosis of the disease since late 1980s–early 1990s due to the introduction of new therapies, firstly angiotensin converting enzyme (ACE) inhibitors for the treatment of the scleroderma renal crisis (SRC) and, in late 1990s-early 2000s, due to the implementation of pulmonary arterial hypertension (PAH) treatment with new drugs such as phosphodiesterase five (PDE5) inhibitors and antagonists of the receptor of endothelin (AREs). Survival has improved over time, measured at any time of the follow-up, from onset (in most studies described in the form of Raynaud’s phenomenon) as well as from diagnosis and what is more important is that it keeps improving. This is true that survival in all stages has improved but especially 1-year and 5-year survival. Since late death is related the most to SSc-non-related causes, it might be reflecting the fact that physicians are improving significantly the prognosis of SSc-related involvements but not that much in other SSc-non-related diseases. Thus, just like in other autoimmune diseases, scleroderma is becoming step-by-step a chronic disease and not a terminal and deleterious diagnosis.

Prior to the assessment of survival of any cohort, we must pay attention to the methodology of the study because there is a huge variability among them, sometimes assessing survival from diagnosis and sometimes from the onset of disease. These last data are obviously a more imprecise data but certainly more real. Several survival and mortality studies from single cohorts and reviews have been published from the last mid-century, reporting data about cumulative survival at different times of follow-up and measured sometimes from the onset of disease and sometimes from the time of diagnosis (Table 1) [142].

StudyCountryYears (mid-cohort)1-year survival5-year survival10-year survival20-year survivalFrom onset/diagnosis
Tuffanelli [1]The USA1935–1958(46)NA70.3%69%NADiagnosis
Farmer [2]The USA1945–1952(48)NA53%NANADiagnosis
Bennet [3]The UK1947–1970(58)94%73%50%NADiagnosis
Medsger [4]The USA1955–1970(62)78%48%NANADiagnosis
Zarafonetis [5]The USA1948–1980(64)NA81.4%69.4%NADiagnosis
Medsger [6]The USA1963–1970(66)70%44%NANADiagnosis
Rowell [7]The UK1960–1975(67)NANA74%NAOnset (first Raynaud)
Barnett [8]AUS1953–1983(68)NA83.6%59.3%27.1%Onset (first Raynaud)
Gouet [9]FR1960–1984(72)88%62.5%50.5%NADiagnosis
Giordano [10]ITA1965–1983(74)NA72%32%NADiagnosis
Altman [11]The USA1973–1977(75)NA63%42%NADiagnosis
Eason [12]NZ1970–1980(75)85%60%42%NADiagnosis
Wynn [13]The USA1970–1980(75)98.4%68.9%51.2%31.7%Diagnosis
Peters-Golden [14]The USA1972–1983(77)84%66%60%NADiagnosis
Ferri [15]ITA1955–1999(77)NA83%69.2%45.5%Diagnosis
Lally [16]The USA1972–1984(78)NA77%NANADiagnosis
Jacobsen [17]DEN1960–1996(78)NA81%71%42%Onset (first non-Raynaud’s symptom)
Kuwana [18]JAP1971–1990(80)NANANANADiagnosis
Geirsson [19]ICE1975–1990(82)NA100%81%NADiagnosis
Kaburaki [20]JAP1976–1991(83)NA78%68.2%NADiagnosis
Nishioka [21]JAP1974–1994(84)NA93.7%82%56.7%Onset (first Raynaud)
Simeón [22]SPA1976–1996(86)NA71%64%62%Onset (first Raynaud)
Bulpitt [23]The USA1982–1992(87)92%68%NANAOnset (first non-Raynaud’s symptom)
Bryan [24]The UK1982–1992(87)NA87%75%NAOnset (first non-Raynaud’s symptom)
Nagy [25]HUN1982–1993(87)NA82.9%70.4%NAOnset (first non-Raynaud’s symptom)
Hesselstrand [26]SWE1983–1995(89)NA92%78%NAOnset (first non-Raynaud’s symptom)
NA86%69%NADiagnosis
Kim [27]KOR1972–2007(89)NA85.4%80.1%NADiagnosis
Mayes [28]The USA1989–1991(90)NA77.9%55.1%26.8%Diagnosis
Hashimoto [29]JAP1973–2008(90)NANA88%77.4%Onset (first Raynaud)
Pérez-Bocanegra [30]SPA1976–2007(91)NA89%81%63%Diagnosis
Alamanos [31]GRE1981–2002(91)NA83%70%NADiagnosis
Nihtyanova [32]The UK1990–1993(91)NA84.2%NANADiagnosis
2000–2003(01)NA89.9%NANAOnset (first non-Raynaud’s symptom)
Joven [33]SPA1980–2006(93)95%85%75%55%Onset (first non-Raynaud’s symptom)
Ruangjutipopan [34]THAI1987–2001(94)NA73%67.4%NAOnset (no definition)
Czirják [35]HUN1983–2005(94)NA84%72.6%NADiagnosis
Arias-Núñez [36]SPA1988–2006(97)NA83.9%64.9%NADiagnosis
Alba [37]SPA1986–2010(98)NA90.7%NANADiagnosis
Al-Dhaher [38]CAN1994–2004(99)NA90%82%NADiagnosis
Sampaio-Barros [39]BRA1991–2010(00)NA90%84%NAOnset (no definition)
Hoffmann-Vold [40]NOR1999–2009(04)NA95%86%NAOnset (first non-Raynaud’s symptom)
Vettori [41]ITA2000–2008(04)NA94.8NANAOnset (first Raynaud)
Kuo [42]TAIW2002–2007(05)94.9%83.2%NANADiagnosis

Table 1.

Survival studies on scleroderma [43].

NA: non-available. Reprinted from Rubio-Rivas et al. [43], with permission from Elsevier.

We show data previously released in Seminars in Arthritis and Rheumatism in the last and more precise meta-analysis, so that we can currently predict at the time of diagnosis: a 1-year survival, 94.9; a 5-year survival, 84.4; a 10-year survival, 70.9 and a 20-year survival, 44.9% (Table 2 and Figure 1) [43].

Survival from onset (first Raynaud)Survival from onset (first non-Raynaud’s symptom)Survival from diagnosis
Before 1990 (five studies)After 1990 (three studies)pBefore 1990 (four studies)After 1990 (three studies)pBefore 1990 (18 studies)After 1990 (eight studies)p
Number of patients840169384680243653476
1-year survival% mean (SD)92 (NA)95 (NA)85.3(9.5)94.9(NA)0.384
5-year survival% mean (SD)85.1(10.4)92.8(2.9)0.38579.7 (8.2)90 (5.0)0.11870.6(14.3)84.4(3.8)0.001
10-year survival% mean (SD)71.5(9.5)88(NA)0.18972.1 (2.5)80.5 (7.8)0.35858.8(14.8)70.9(10.1)0.086
20-year survival% mean (SD)48.6(18.8)77.4(NA)0.31642 (NA)55 (NA)38.6(9.8)44.9(25.6)0.790

Table 2.

Survival studies on scleroderma [43].

T-test for independent groups among studies before and after 1990 (mid-cohort year). NA: non-available. Reprinted from Rubio-Rivas et al. [43], with permission from Elsevier.

Figure 1.

Survival evolution over time. Meta-regression. Five-year survival (coefficient b = 0.308 and p = 0.402) and 10-year survival (coefficient b = 0.595 and p = 0.237) from the onset (first Raynaud). Five-year survival (coefficient b = 0.612 and p = 0.113) and 10-year survival (coefficient b = 0.590 and p = 0.037) from the onset (first non-Raynaud’s symptom). Five-year survival (coefficient b = 0.595 and p < 0.001) and 10-year survival (coefficient b = 0.536 and p = 0.025) from diagnosis. Reprinted from Rubio-Rivas et al., with permission from Elsevier [43].

Advertisement

3. Mortality

SSc is an autoimmune disease with a broad spectrum of severity, ranging from a mild disease to a devastating one. The most valuable parameter in order to compare mortality (instead of a crude mortality rate) is the assessment of the SMR, a fundamental tool in the only five mortality meta-analyses reported so far in SSc (Table 3). The SMR is the ratio between observed mortality and expected mortality in sex- and age-matched general population. These five meta-analyses are based on the assessment of the SMR: Elhai et al. {nine studies, overall SMR is 3.53 (3.03–4.11)} [45], Loannidis et al. {seven studies} [44], Toledano et al. {seven studies, overall SMR 3.51 (2.74–4.50)} [46], Komócsi et al. {10 studies, overall SMR 3.24} [47] and Rubio-Rivas et al. {17 studies, overall SMR 2.72 (1.90–3.83)} [43]. In base of this last study based on 17 studies, we could state that mortality is over 2.7-fold compared to the general population (Table 4 and Figure 2) [5, 17, 24, 26, 29, 30, 31, 33, 37, 40, 42, 4853]. Mortality has been decreasing over time and notoriously after 1990, being more reasonable to accept nowadays an SMR over 2.4-fold in a patient diagnosed today (Figure 2). Obviously, prognosis should be individualized since different risk factors present at diagnosis or during the follow-up can modify this predicted SMR. For instance, SMR in males and dcSSc subset is expected to be worse compared to SMR in females or lcSSc subset (Figure 3).

Figure 2.

SMR meta-analysis. The overall SMR (discontinuous points) is 2.71 (1.95–3.75). SMR before 1990 (continuous line) is 3.33 (1.64–6.75). SMR after 1990 (discontinuous lines) is 2.42 (1.89–3.11). Forest plot. Meta-regression of change in SMR (lnSMR) with mid-cohort year (Coefficient b = –0.055 and p = 0.064). Reprinted from Rubio-Rivas et al., with permission from Elsevier [43].

Figure 3.

SMR meta-analysis. For the male gender, overall SMR is 3.18 (2.62–3.85) and for the female gender, overall SMR is 2.81 (2.25–3.50); for dcSSc subtype, the overall SMR is 4.73 (3.69–6.07) and for lcSSc subtype, overall SMR is 2.04 (1.55–2.68). Forest plot. Reprinted from Rubio-Rivas et al., with permission from Elsevier [43].

StudyYear of publicationNumber of studies includedSMR (95% CI)
Ioannidis et al. [44]20057
Elhai et al. [45]201293.53 (3.03–4.11)
Toledano et al. [46]201273.51 (2.74–4.50)
Komócsi et al. [47]2012103.24 (NA)
Rubio-Rivas et al. [43]2014172.72 (1.93–3.83)

Table 3.

Meta-analyses on scleroderma and mortality.

NA: non-available.

StudyCountryYears (mid-cohort year)DeathOverall SMR (95%CI)dcSSc SMR (95%CI)lcSSc SMR (95%CI)Male SMR (95%CI)Female SMR (95%CI)
Zarafonetis [5]US1948–1980 (64)1425.40 (3.17-7.63)NANANANA
Jacobsen [17]DEN1960–1996 (78)1602.90 (2.50-3.40)4.50 (3.50-5.70)2.30 (1.80-2.80)3.70 (2.70-5.10)2.70 (2.30-3.30)
Abu-Shakra [48]CAN1976–1990 (83)614.69 (3.73-5.65)6.18 (4.17-8.81)3.80 (2.58-5.39)4.18 (2.09-7.48)4.81 (3.65-6.44)
Walsh [49]US1981–1990 (85)21231.05 (1.01-1.1)NANANANA
Bryan [24]UK1982–1992 (87)554.05 (3.03-5.22)NANA3.22 (1.85-4.97)4.59 (3.22-6.19)
Hesselstrand [26]SWE1983–1995 (89)494.59 (3.48-6.07)6.06 (4.09-9.02)3.72 (2.41-532)4.77 (3.21-7.09)4.44 (2.87-6.34)
Hashimoto [29]JAP1973–1908 (90)862.76 (2.18-3.35)5.90 (4.20-7.61)1.71 (1.18-2.24)3.31 (1.15-5.47)2.71 (2.10-3.32)
Alamanos [31]GRE1981–2002 (91)362.0 (1.2-2.8)NANANANA
Scussel-Lonzetti [50]CAN1984–1999 (91)662.69 (2.10-3.40)6.17 (2.80-11.70)2.71 (1.85-3.80)1.76 (0.80-3.30)2.55 (1.90-3.30)
Pérez-Bocanegra [30]SPA1976–2007 (91)731.90 (1.50-2.30)6.50 (4.10-9.80)1.70 (1.20-2.20)1.80 (0.80-3.40)2.50 (1.90-3.20)
Joven [33]SPA1980–2006 (93)443.10 (1.60-6.10)NANANANA
Alba [37]SPA1986–2010 (98)1513.80 (3.18-4.43)NANANANA
Hissaria [51]AUS1993–2007 (00)3311.46 (1.28-1.69)2.92 (2.20-3.89)1.30 (1.11-1.53)NANA
Mok [52]CHI1999–2008 (03)1103.94 (3.20-4.68)NANA2.59 (1.32-3.87)4.32 (3.45-5.20)
Hoffmann-Vold [40]NOR1999–2009 (04)432.03 (1.40-2.60)5.33 (3.90-10.30)1.62 (1.10-2.50)2.61 (1.40-3.90)1.80 (1.20-2.70)
Strickland [53]UK1999–2010 (04)531.34 (0.95-1.74)1.66 (0.83-2.97)1.27 (0.92-1.72)1.54 (0.67-3.04)1.30 (0.95-1.74)
Kuo [42]TAIW2002–2007 (05)2043.24 (2.82-3.71)NANA3.53 (2.97-4.16)2.92 (2.29-3.66)

Table 4.

Studies included in the SMR meta-analysis by Rubio-Rivas et al [43].

NA: non-available, SMR: standardized mortality ratio, dcSSc: diffuse cutaneous systemic sclerosis and lcSSc: limited cutaneous systemic sclerosis. Reprinted from Rubio-Rivas et al. [43], with permission from Elsevier.

Advertisement

4. Causes of death

As in other autoimmune diseases, the pattern of mortality has been changing over time since the autoimmune disease by itself has been the main cause of death in these patients for ages but the more physicians control the disease, the more likely it is to die due to other causes not directly related to SSc [43, 5456].

4.1. SSc-related causes of death

Among the SSc-related causes, there are four major organs potentially involved: the lungs, heart, kidneys and gastrointestinal tract. Among them, lung and renal involvement were the most important as a cause of death during the twentieth century (Table 5) [2, 3, 7, 8, 1113, 15, 1719, 2124, 26, 29, 31, 3342, 48, 5053, 56, 57, 5962].

CountryYears (mid-cohort year)Deads/nSSc-related deathLung deathHeart deathKidney deathGI death
Farmer [2]US1945–1952 (48)115/271 (49%)17 (14.8%)5 (29.4%)6 (35.3%)1 (5.9%)1 (5.9%)
Bennet [3]UK1947–1970 (58)26/67 (38.8%)1 (9.1%)0 (0%)1 (9.1%)0 (0%)0 (0%)
Rowell [7]UK1960–1975 (67)22/84 (26.2%)NANANANANA
Barnett [8]AUS1953–1983 (68)86/177 (48.6%)42 (48.8%)8 (19%)10 (11.6%)16 (38.1%)8 (9.3%)
Altman [11]US1973–1977 (75)131/264 (49.6%)89 (68%)19 (21.3%)19 (21.3%)35 (39.3%)13 (14.6%)
Eason [12]NZ1970–1980 (75)24/47 (51%)18 (75%)7 (38.9%)4 (22.2%)5 (27.8%)2 (11.1%)
Wynn [13]US1970–1980 (75)25/64 (39.1%)17 (68%)7 (41.2%)6 (35.3%)4 (23.5%)0 (0%)
Ferri [15]ITA1955–1999 (77)279/1012 (27.6%)61 (35.9%)NANANANA
Lally [16]US1972–1984 (78)17/91 (18.7%)14 (82.4%)0 (0%)8 (57.1%)6 (42.9%)0 (0%)
Jacobsen [17]DEN1960–1996 (78)160/344 (46.5%)41 (25.6%)13 (31.7%)1 (2.4%)17 (41.5%)9 (22%)
Kuwana [18]JAP1971–1990 (80)51/275 (18.5%)32 (62.7%)23 (71.9%)4 (12.5%)5 (15.6%)0 (0%)
Geirsson [19]ICE1975–1990 (82)5/23 (21.7%)2 (40%)0 (0%)1 (50%)1 (50%)0 (0%)
Abu-Shakra [48]CAN1976–1990 (83)61/237 (25.7%)44 (77.1%)13 (29.5%)5 (11.4%)5 (11.4%)0 (0%)
Nishioka [21]JAP1974–1994 (84)90/496 (18.1%)64 (71.1%)44 (68.8%)31 (48.4%)12 (18.8%)13 (20.3%)
Steen [56]US1972–1996 (84)364/1508 (24.1%)182 (50%)NANANANA
Simeón [22]SPA1976–1996 (86)12/79 (15.2%)11 (91.7%)4 (36.4%)0 (0%)7 (63.6%)0 (0%)
Bulpitt [23]US1982–1992 (87)15/48 (31.3%)9 (60%)4 (44.4%)1 (11.1%)4 (44.4%)0 (0%)
Bryan [24]UK1982–1992 (87)55/283 (19.4%)34 (61.8%)15 (44.1%)5 (14.7%)5 (14.7%)3 (8.8%)
Geirsson [57]SWE1982–1995 (88)30/100 (30%)10 (33.3%)5 (50%)4 (40%)1 (10%)0 (0%)
Hesselstrand [26]SWE1983–1995 (89)49/249 (19.7%)15 (30.6%)10 (66.7%)1 (6.7%)1 (6.7%)3 (20%)
Bond [58]AUS1983–1996 (89)123/123 (100%)43 (35%)13 (30.2%)14 (32.6%)6 (14%)NA
Vlachoyiannopoulos [59]GRE1982–1996 (89)7/254 (2.8%)6 (85.7%)2 (33.3%)2 (33.3%)2 (33.3%)0 (0%)
Hashimoto [29]JAP1973–1908 (90)86/405 (21.2%)NANANANANA
Scussel-Lonzetti [50]CAN1984–1999 (91)66/309 (21.4%)35 (53%)6 (17.1%)4 (11.4%)7 (20%)3 (8.6%)
Alamanos [31]GRE1981–2002 (91)36/109 (33%)23 (63.9%)21 (58.3%)21 (58.3%)2 (5.6%)0 (0%)
Joven [33]SPA1980–1906 (93)44/204 (21.6%)36 (82%)20 (55.6%)8 (22.2%)1 (2.8%)3 (8.3%)
Ruangjutipopan [34]THAI1987–2001 (94)31/222 (26.7%)18 (58.1%)NANANA0 (0%)
Czirják [35]HUN1983–-2005 (94)93/366 (25.4%)86 (92.5%)30 (34.9%)29 (33.7%)16 (18.6%)8 (9.3%)
Derk [60]US1985–2007 (96)87/87 (100%)67 (77%)65 (97%)55 (82.1%)2 (3%)0 (0%)
Arias-Núñez [36]SPA1988–2006 (97)20/78 (25.6%)11 (55%)10 (90.9%)1 (9.1%)0 (0%)0 (0%)
Alba [37]SPA1986–2010 (98)151/1037 (14.6%)61 (78.2%)NA13 (16.7%)0 (0%)5 (4.1%)
Al-Dhaher [38]CAN1994–2004 (99)42/185 (23%)NA15 (45.5%)9 (27.3%)9 (27.3%)0 (0%)
Sampaio-Barros [39]BRA1991–2010 (00)168/947 (17.7%)110 (65.5%)53 (48.2%)27 (24.5%)12 (10.9%)5 (4.5%)
Assassi [61]US1998–2008 (03)52/250 (20.8%)29 (55.8%)10 (34.5%)4 (13.8%)NA2 (6.9%)
Mok [52]CHI1999–2008 (03)110/449 (24.5%)26 (24%)11 (42.3%)NA5 (19.2%)2 (7.7%)
Hoffmann-Vold [40]NOR1999–2009 (04)43/312 (13.8%)13 (54.2%)0 (0%)5 (20.8%)6 (25%)2 (4.7%)
Vettori [41]ITA2000–2008 (04)20/251 (8%)12 (60%)5 (41.7%)4 (33.3%)1 (8.3%)2 (16.7%)
Hachulla [62]FR2002–2006 (04)47/546 (8.6%)24 (51.1%)19 (79.2%)0 (0%)3 (12.5%)2 (8.3%)
Strickland [53]UK1999–2010 (04)53/204 (26%)19 (35.9%)9 (47.4%)4 (21.1%)0 (0%)1 (5.3%)
Kuo [42]TAIW2002–2007 (05)204/1479 (13.8%)57 (27.9%)9 (4.4%)29 (0.1%)14 (6.9%)10 (5%)

Table 5.

SSc-related causes of death in medical literature [43].

Lung, heart, kidney and GI are deaths related to SSc. NA: non-available; GI: gastrointestinal. Reprinted from Rubio-Rivas et al. [43], with permission from Elsevier.

4.1.1. Lung involvement

In the case of lung involvement, death can be due to the progression towards respiratory failure due to PAH or interstitial lung disease (ILD).

In the case of PAH, evidence suggests that SSc-PAH patients have a worse response to therapy when compared to idiopathic PAH. New therapies (phosphodiesterase type 5 inhibitors and endothelin receptor antagonists) have improved its prognosis but not that much and thus, this is still a severe manifestation of the disease and a frequent cause of death. An early combination schedule of treatment has been suggested to be better in terms of prognosis. However, more studies are required to demonstrate and standardize this strategy of treatment [63].

Interstitial lung disease constitutes the most severe manifestation of the disease and is in fact the first cause of death in these patients (Figure 4). Therefore, it is crucial to perform a regular screening of this involvement and an early treatment when diagnosed. Patients showing the following criteria would warrant an immunosuppressive treatment: (1) either an extent of lung disease >20% on High-resolution computed tomography (HRCT) or an indeterminate extent (disease extent not readily classifiable as minimal or severe; HRCT extent is 10–30%) of disease plus an FVC < 70%, (2) patients experiencing a significant decrease in pulmonary functional assessment during the follow-up (FVC > 10% or DLco >15% or both, whatever the extent of lung involvement is for 12 months). Currently, the management of SSc–ILD is largely confined to immunomodulvation. Non-selective immunosuppressants such as cyclophosphamide followed by mycophenolate mofetil and azathioprine are still the most widely used medications in SSc-ILD. Several alternative approaches may be considered, including B cell depletion therapies (rituximab), anti-TGF-β antibody, tyrosine kinase inhibitors (imatinib, dasatinib), anti-IL-6 antibody, anti-IL-13 antibody, pirfenidone and haematopoietic stem cell transplantation (HSCT). Finally, lung transplantation may be limited to those patients, with severe SSc-ILD, unresponsive to pharmacologic therapy  [64]. It is important to remember that, although often used, during the first stages of treatment, prednisone doses over 15 mg a day can be dangerous in order to trigger a scleroderma renal crisis.

Figure 4.

Meta-regression of deaths due to lung over time (coefficient b = 0.935 and p = 0.005) and renal (coefficient b=−0.206 and p = 0.352). Reprinted from Rubio-Rivas et al., with permission from Elsevier [43].

4.1.2. Renal involvement

Scleroderma renal crisis occurs during the rapid progression of skin thickening in the early stages of dcSSc (<5 years after disease onset). Several case series published during the past 20 years and a 2013 systematic literature review has estimated that SRC develops in 5–15 and 15% of patients with dcSSc, respectively. Interestingly, the incidence and prevalence of SRC seem to be decreasing over time, possibly as a result of early recognition and management of SRC risk factors and early signs and symptoms in patients with dcSSc [65]. The introduction of ACE inhibitors (captopril) reduced dramatically its frequency as the cause of death since early 1990s of the past century (Figure 4). Besides, its incidence is decreasing but due to unknown reasons. The extended use of ACE inhibitors prescribed for other reasons (i.e. arterial hypertension or heart failure) has not been found as the cause of this decreasing incidence.

4.1.3. Heart involvement

Despite the fact that definite SSc for cardiac involvement does not exist, we could categorize its involvement in five major groups: pericarditis with or without cardiac tamponade, ischemic cardiopathy (documented myocardial infarction, angina, ischemic alterations in myocardial perfusion SPECT or requirement of coronary revascularization, surgical or percutaneous), pacemaker bearing regardless of the time of arrhythmia, sudden death and congestive heart failure [66]. As it is more recognized nowadays, its ratio is increasing, but the real challenge in the years to come shall be to distinguish the real scleroderma involvement from a cardiac SSc-non-related involvement. Anyway, we can hypothesize today that this is related to SSc in younger patients without classical cardiovascular risk factors.

4.1.4. Gastrointestinal involvement

The gastrointestinal tract is the most affected organ after the skin and can be affected from the oral cavity to the anus. About 90% of all patients will be affected during follow-up. This involvement can result in a decreased quality of life more often than a direct cause of death. In fact, it has been a rare cause of death over time. The few fatal cases have been related to those with severe intestinal involvement leading to malabsorption and secondary starvation. We cannot forget the possible role of the oesophageal involvement in the development of interstitial lung disease [67].

4.2. SSc-non-related causes of death

Among SSc-non-related causes of death, we can find three major diseases: cancer, infections and cardiovascular diseases (Table 6) [2, 3, 7, 8, 1113, 15, 1719, 2124, 26, 29, 31, 3342, 48, 5053, 56, 57, 5962].

4.2.1. Cancer

A higher standardized incidence ratio (SIR) of cancer in these patients not only compared to the general population that could be related to immunosuppressive treatment but also to the self-nature of the disease has been described [68]. In fact, those cancers diagnosed within the first 3 years after the diagnosis of scleroderma have been suggested to be classified as SSc-related causes. Cancer among SSc patients with RNA polymerase III antibodies has been reported to be in a close temporal relationship to the onset of SSc (first 36 months after the onset of SSc), which supports the paraneoplastic phenomenon in this subset of patients [69]. Thus, it is recommended to rule out this possibility at the time of the diagnosis, although protocol for this purpose has not been standardized so far. Cancers most frequently found in SSc patients are those from breast, blood, lung, gastrointestinal tract, genitourinary tract and skin and, out of these, those most related to the presence of RNAp III antibodies were breast cancer, skin cancer and genitourinary cancer [69].

4.2.2. Infections

Risk factors associated with infections in patients diagnosed with scleroderma include oesophageal (increased risk for aspiration pneumonia) and interstitial lung disease (increased risk for pneumonia), severe Raynaud’s phenomenon or calcinosis (risk for localized superinfections) and the use of specific treatments for the management of the disease. Bacterial infections due to Gram-positive bacilli have been described, especially in patients with severe Raynaud or calcinosis. In patients receiving immunosuppressive treatment, especially corticosteroids, Nocardia sp. and Mycobacteria sp. must be taken into account. A few viruses such as Epstein-Barr virus and CMV have been described as triggering the onset of scleroderma, and Parvovirus B19 DNA has been detected in patients who have scleroderma, but the clinical correlate of this finding is unclear. Finally, among fungi, Pneumocystis jirovecii pneumonia has been reported in some patients who have scleroderma [70]. Aspergillus sp. has been rarely reported in scleroderma, but in any patient under cellular immunosuppression has to be taken into account as well [71].

4.2.3. Cardiovascular disease

Scleroderma, as other autoimmune diseases, shows up as an inflammatory background that leads to the fibroblast activation. This background is more visual in the first stages of the skin or lung involvement, but it is thought to happen elsewhere. Thus, scleroderma itself can be understood as a new cardiovascular risk factor not only involved in the development of microvascular disease but also of macrovascular disease [72]. Atherosclerosis has been found to be increased in patients with SSc in all territories: coronary arteries, carotid arteries, cerebrovascular vessels and peripheral arteries [72]. This is the most controversial group of diseases in terms of classification since it is a challenge to differentiate whether it is an SSc-related or a SSc-non-related event. Although sometimes undistinguishable, currently, the clinical context has been hypothesized to aid for this purpose. Thus, in young patients without other classical cardiovascular risk factors (smoking behaviour, diabetes mellitus, arterial hypertension, hyperlipidaemia, obesity), we state that a particular event should be classified as SSc-related.

According to the latest studies [43], the big picture when talking about causes of death should be that SSc-related death is estimated nowadays in 56.7% of all deaths. Among them, representing lung death 57%, heart death 28.2%, renal death 11.7% and gastrointestinal death 6.4% (Table 7). In contrast, SSc-non-related death is estimated in 43.3% of all patients and among them being cancer, infections and cardiovascular disease the leading cause of SSc-non-related death.

CountryYears (mid-cohort)Deads/nCancer deathInfection deathAtherosclerosis death
Farmer [2]US1945–1952 (48)115/271 (49%)6 (5.2%)4 (3.5%)20 (17.4%)
Bennet [3]UK1947–1970 (58)26/67 (38.8%)2 (18.2%)3 (27.3%)5 (45.5%)
Rowell [7]UK1960–1975 (67)22/84 (26.2%)0 (0%)NA1 (4.5%)
Barnett [8]AUS1953–1983 (68)86/177 (48.6%)NANANA
Altman [11]US1973–1977 (75)131/264 (49.6%)9 (6.9%)3 (2.3%)17 (13%)
Eason [12]NZ1970–1980 (75)24/47 (51%)2 (8.3%)2 (8.3%)2 (8.3%)
Wynn [13]US1970–1980 (75)25/64 (39.1%)3 (12%)0 (0%)3 (12%)
Ferri [15]ITA1955–1999 (77)279/1012 (27.6%)25 (14.7%)NA
Lally [16]US1972–1984 (78)17/91 (18.7%)1 (5.9%)2 (11.8%)0 (0%)
Jacobsen [17]DEN1960–1996 (78)160/344 (46.5%)30 (18.8%)19 (11.9 %)43/160
Kuwana [18]JAP1971–1990 (80)51/275 (18.5%)5 (9.8%)1 (2%)5 (9.8%)
Geirsson [19]ICE1975–1990 (82)5/23 (21.7%)1 (20%)0 (0%)2 (40%)
Abu-Shakra [48]CAN1976–1990 (83)61/237 (25.7%)6 (9.8%)0 (0%)NA
Nishioka [21]JAP1974–1994 (84)90/496 (18.1%)21 (23.3%)5 (5.6%)NA
Steen [56]US1972–1996 (84)364/1508 (24.1%)63 (17.3%)32 (8.8%)30 (8.2%)
Simeón [22]SPA1976–1996 (86)12/79 (15.2%)1 (8.3%)0 (0%)0 (0%)
Bulpitt [23]US1982–1992 (87)15/48 (31.3%)1 (6.7%)1 (6.7%)0 (0%)
Bryan [24]UK1982–1992 (87)55/283 (19.4%)1 (1.8%)4 (7.3%)11 (20%)
Geirsson [57]SWE1982–1995 (88)30/100 (30%)9 (30%)6 (20%)3 (10%)
Hesselstrand [26]SWE1983–1995 (89)49/249 (19.7%)12 (24.5%)9 (18.4%)9 (18.4%)
Bond [58]AUS1983–1996 (89)123/123 (100%)10 (8.1%)6 (4.9%)17 (13.8%)
Vlachoyiannopoulos [59]GRE1982–1996 (89)7/254 (2.8%)0 (0%)0 (0%)0 (0%)
Hashimoto [29]JAP1973–2008 (90)86/405 (21.2%)19 (22.1%)14 (16.3%)NA
Scussel-Lonzetti [50]CAN1984–1999 (91)66/309 (21.4%)13 (19.7%)NA10 (15.2%)
Alamanos [31]GRE1981–2002 (91)36/109 (33%)4 (11.1%)1 (0.2%)6 (16.7%)
Joven [33]SPA1980–2006 (93)44/204 (21.6%)3 (6.8%)2 (4.5%)5 (11.4%)
Ruangjutipopan [34]THAI1987–2001 (94)31/222 (26.7%)0 (0%)13 (42%)0 (0%)
Czirják [35]HUN1983–2005 (94)93/366 (25.4%)12 (12.9%)2 (2.2%)NA
Derk [60]US1985–2007 (96)87/87 (100%)3 (4.5%)4.6%0 (0%)
Arias-Núñez [36]SPA1988–2006 (97)20/78 (25.6%)1 (5%)3 (15%)2 (10%)
Alba [37]SPA1986–2010 (98)151/1037 (14.6%)61 (78.2%)18 (14.8%)NA
Al-Dhaher [38]CAN1994–2004 (99)42/185 (23%)NANANA
Sampaio-Barros [39]BRA1991–2010 (00)168/947 (17.7%)8 (4.8%)24 (14.3%)8 (4.8%)
Assassi [61]US1998–2008 (03)52/250 (20.8%)NANANA
Mok [52]CHI1999–2008 (03)110/449 (24.5%)11 (10%)19 (17.3%)NA
Hoffmann-Vold [40]NOR1999–2009 (04)43/312 (13.8%)13 (54.2%)6 (14%)4 (9.3%)
Vettori [41]ITA2000–2008 (04)20/251 (8%)2 (10%)1 (5%)2 (10%)
Hachulla [63]FR2002–2006 (04)47/546 (8.6%)8 (17%)4 (8.5%)2 (4.3%)
Strickland [53]UK1999–2010 (04)53/204 (26%)10 (18.9%)13(24.5%)12 (22.6%)
Kuo [42]TAIW2002–2007 (05)204/1479 (13.8%)30 (14.7%)12 (5.9%)29 (14.2%)

Table 6.

SSc-non-related causes of death in medical literature [43].

Reprinted from Rubio-Rivas et al. [43], with permission from Elsevier.

Before 1990 (22 studies)After 1990 (18 studies)p
SSc-related deaths % mean (SD)52.5 (24.7)56.7 (17.4)0.544
Lung34.5 (21.3)57.0 (24.7)0.008
Heart29.3 (23.8)28.2 (28.1)0.905
Kidney26.4 (17.6)11.7 (7.9)0.003
GI6.8 (8.7)6.4 (7.0)0.881

Table 7.

SSc-related causes of death [43].

T-test for independent groups among studies before and after 1990 (mid-cohort year). GI: gastrointestinal. Reprinted from Rubio-Rivas et al. [43], with permission from Elsevier.

4.3. A temporary pattern of SSc-related causes of death

In general, we could state that early death within the first years after the diagnosis of scleroderma is primarily due to the autoimmune disease itself, and late death is due to SSc-non directly related causes. Besides, this progression is currently even more notorious since data from the Spanish Registry show the fact that beyond 10 years after diagnosis, 83% of all deaths are due to SSc-non-related causes, supporting the idea that by struggling with the disease in the first years could save quite a few deaths due to the self-disease [54, 55].

Among these SSc-related causes, pulmonary death (due to ILD or PAH) has been and still currently is the leading SSc-related cause of death in all stages of the disease. In contrast, renal death was the second cause of the death in the past and most of all in the dcSSc subset and within the first 5 years after SSc diagnosis, but, in the last years, we have been witnesses of an important decrease of renal death rate. Heart death is at first sight more present nowadays and within the early stages of the disease but possibly due to a better understanding and knowledge of this involvement. Gastrointestinal death has been the cause of death only inisolated cases over time (Table 8).

Cause of death1990–19992000–2009p
EarlySSc-non-related3 (17.6%)23 (48.9%)0.042
Pulmonary8 (47.1%)16 (34.0%)0.390
Renal6 (35.3%)1 (2.1%)< 0.001
Cardiac0 (0.0%)7 (14.9%)0.175
Gastrointestinal0 (0.0%)0 (0.0%)
IntermediateSSc-non-related5 (23.8%)11 (50.0%)0.116
Pulmonary13 (61.9%)6 (27.3%)0.033
Renal1 (4.8%)1 (4.5%)1.000
Cardiac2 (9.5%)4 (18.2%)0.664
Gastrointestinal0 (0.0%)0 (0.0%)
LateSSc-non-related10 (37.0%)5 (83.3%)0.070
Pulmonary11 (40.7%)1 (16.7%)0.379
Renal1 (3.7%)0 (0.0%)1.000
Cardiac4 (14.8%)0 (0.0%)1.000
Gastrointestinal1 (3.7%)0 (0.0%)1.000

Table 8.

SSc-non-related and SSc-related (lung, heart, renal and gastrointestinal) causes of death. In bold, p-values reaching statistical significance or close to significance.

Early (first 5 years after diagnosis), intermediate (5–10 years after diagnosis) and late death ( >10 years after diagnosis) from the Spanish Scleroderma Network. Reprinted from Rubio-Rivas [54].

Thus, it is expected to see an increasing rate of SSc-non-related causes in the years to come, mainly cancer and cardiovascular causes. Among the SSc-related causes, cardiovascular causes will be the cornerstone and the challenge will be to distinguish SSc-related and SSc-non-related cardiovascular events.

Advertisement

5. Risk factors of poor outcome

To date, several risk factors have been identified related to poor prognosis, sometimes reported as a result of univariate analysis and sometimes as a result of multivariate analysis [43].

Taking into account the number of citations from the different studies (Figure 5), more cited risk factors would be an older age at diagnosis, dcSSc subset, male gender and visceral involvement (most of all lung, heart and renal involvement).

Figure 5.

Risk factors for poor outcomes (number of citations in the different studies). Into “others” are included proteinuria, gastrointestinal and osteoarticular involvement, high BUN, hypo/hyperpigmentation, digital ulcers, HLADQA1 and HLA DRB1, low body mass index, hands deformity, low STC and low total lung compliance, myositis, anti-RNP +, S3 heart gallop, corticosteroid treatment, longer time from first Raynaud, no CREST, tobacco and alcohol uptake and hypoproteinaemia. Reprinted from Rubio-Rivas et al., with permission from Elsevier [43].

It is not easy to quantify the overall risk attributed to any of these factors since they have been described in different ways, but by meta-analysing those described homogeneously (Figure 6), we could state a hazard ratio for kidney involvement 4.22 (3.42–5.19), for heart involvement 3.43 (1.35–8.70), for ILD 2.89 (2.24–3.72), for high eritrosedimentation rate 2.77 (2.06–3.71), for PAH 2.62 (1.64–4.17), for dcSSc 2.28 (1.69–3.08), for male gender 1.88 (1.48–2.38) and age/year 1.05 (1.04–1.06) [43].

Figure 6.

A quantitative meta-analysis of the main risk factors related to mortality. Reprinted from Rubio-Rivas et al., with permission from Elsevier [43].

New risk factors are required in order to identify those patients with worse prognosis who could get some benefits in terms of a more aggressive therapy and/or closer follow-up. Recently, the mode of onset has been evaluated as a potential risk factor, finding a worse prognosis in those patients with an onset in the form of non-Raynaud’s phenomenon, with the only exception of arthralgia (data not yet released).

Anyway, the risk should be individualized and accordingly lead to the decision-making for every patient. Thus, it should be our aim to create prognosis scales based on these known risk factors.

References

  1. 1. Tuffanelli DL, Winkelmann RK. Systemic scleroderma. A clinical study of 727 cases. Archives of Dermatology. 1961;84(3):359-71
  2. 2. Farmer RG, Gifford RW, Hines EA. Prognostic significance of Raynaud’s phenomenon and other clinical characteristics of systemic scleroderma: A study of 271 cases. Circulation. 1960;21:1088-1095
  3. 3. Bennet R, Bluestone R, Holt PJL. Survival in scleroderma. Annals of the Rheumatic Disease. 1971;30:581-588
  4. 4. Medsger TA, Masi AT. The epidemiology of systemic sclerosis (scleroderma) among male U.S. veterans. International Journal of Chronic Obstructive Pulmonary Disease. 1978;31:73-85
  5. 5. Zarafonetis C, Dabich L, Negri D, Skovronski JJ, DeVol EB, Wolfe R. Retrospective studies in scleroderma: effect of potassium para-aminobenzoate on survival. Journal of Clinical Epidemiology. 1988;41(2):193-205
  6. 6. Medsger TA, Masi AT. Survival with scleroderma. A life-table analysis of clinical and demographic factors in 358 male U.S. veteran patients. International Journal of Chronic Obstructive Pulmonary Disease. 1973;26:647-660
  7. 7. Rowell NR. The prognosis of systemic sclerosis. British Journal of Dermatology. 1976;95:57-60
  8. 8. Barnett AJ, Miller MH, Littlejohn GO. A survival study of patients with scleroderma diagnosed over 30 years (1953-1983): The value of a simple cutaneous classification in the early stages of the disease. The Journal of Rheumatology. 1988;15:276-283
  9. 9. Gouet D, Azais I, Marechaud R, Alcalay M, Barriere H, Bontoux D. Pronostic de la sclérodermie generalise. Étude retrospective de 78 observations. Rev Med Interne. 1986;7:233-41
  10. 10. Giordano M, Valentini G, Migliaresi S, Picillo U, Vatti M. Different antibody patterns and different prognoses in patients with scleroderma with various extent of skin sclerosis. The Journal of Rheumatology. 1986;13:911-916
  11. 11. Altman RD, Medsger TA, Bloch DA, Michel BA. Predictors of survival in systemic sclerosis (scleroderma). Arthritis & Rheumatology. 1991;34(4):403-413
  12. 12. Eason RJ, Tan PL, Gow PJ. Progressive systemic sclerosis in Auckland: A ten year review with emphasis on prognostic features. Australian and New Zealand Journal of Medicine. 1981;11(6):657-662
  13. 13. Wynn J, Fineberg N, Matzer L, Cortada X, Armstrong W, Dillon JC. et al. Prediction of survival in progressive systemic sclerosis by multivariate analysis of clinical features. American Heart Journal. 1985;110:123-127
  14. 14. Peters-Golden M, Wise RA, Hochberg MC, Stevens MB, Wigley FM. Carbon monoxide diffusing capacity as predictor of outcome in systemic sclerosis. American Journal of Medicine. 1984;77:1027-1033
  15. 15. Ferri C, Valentini G, Cozzi F, Sebastiani M, Michelassi C, La Montagna G. Systemic sclerosis. Demographic, clinical and serologic features and survival in 1012 Italian patients. Medicine. 2002;81:139-53
  16. 16. Lally EV, Jiménez SA, Kaplan SR. Progressive systemic sclerosis: mode of presentation, rapidly progressive disease course, and mortality based on an analysis of 91 patients. Seminars in Arthritis and Rheumatism. 1988;18(1):1-13
  17. 17. Jacobsen S, Halberg P, Ullman S. Mortality and causes of death of 344 Danish patients with systemic sclerosis (scleroderma). British Journal of Rheumatology. 1998;37:750-755
  18. 18. Kuwana M, Kaburaki J, Okano Y, Tojo T, Homma M. Clinical and prognostic associations based on serum antinuclear antibodies in Japanese patients with systemic sclerosis. Arthritis & Rheumatology. 1994;37(1):75-83
  19. 19. Geirsson AJ, Steinsson K, Gudmundsson S, Sigurdsson V. Systemic sclerosis in Iceland. A nationwide epidemiological study. Annals of Rheumatic Disease. 1994;53:502-505
  20. 20. Kaburaki J, Lee CC, Kuwana M, Tojo T, Ikeda Y, Takano M et al. Initial predictors of survival in Systemic Sclerosis. The Keio Journal of Medicine. 1992;41(3):141-145
  21. 21. Nishioka K, Katayama I, Kondo H, Shinkai H, Ueki H, Tamaki K et al. Epidemiological analysis of prognosis of 496 Japanese patients with progressive systemic sclerosis. The Journal of Dermatology. 1996;23:677-682
  22. 22. Simeón CP, Armadans L, Fonollosa V, Vilardell M, Candell J, Tolosa C. et al. Survival prognostic factors and markers of morbidity in Spanish patients with systemic sclerosis. Annals of Rheumatic Disease. 1997;56:723-728
  23. 23. Bulpitt KJ, Clements PJ, Lachenbruch PA, Paulus HE, Peter JB, Agopian MS et al. Early undifferentiated connective tissue disease:III. Outcome and prognostic indicators in early scleroderma (systemic sclerosis). Annals of Internal Medicine. 1993;118:602-609
  24. 24. Bryan C, Howard Y, Brennan P, Black C, Silman A. Survival following the onset of scleroderma: results from a retrospective inception cohort study of the UK patient population. British Journal of Rheumatology. 1996;35:1122-1126
  25. 25. Nagy Z, Czirják L. Predictors of survival in 171 patients with systemic sclerosis (Sclero derma). Clinical Rheumatology. 1997;16(5):454-460
  26. 26. Hesselstrand R, Scheja A, Akesson A. Mortality and causes of death in a Swedish series of systemic sclerosis patients. Annals of Rheumatic Diseases. 1998;57:682-686
  27. 27. Kim J, Park SK, Moon KW, Lee EY, Lee YJ, Song YW et al. The prognostic factors of systemic sclerosis for survival among Koreans. Clinical Rheumatology. 2010;29:297-302
  28. 28. Mayes MD, Lacey JV, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis & Rheumatology. 2003;48(8):2246-2255
  29. 29. Hashimoto A, Tejima S, Tono T, Suzuki M, Tanaka S, Matsui T et al. Predictors of survival and causes of death in Japanese patients with systemic sclerosis. The Journal of Rheumatology. 2011;38:1-9
  30. 30. Pérez-Bocanegra C, Solans-Laqué R, Simeón-Aznar CP, Campillo M, Fonollosa V, Vilardell M. Age-related survival and clinical features in systemic sclerosis patients older or younger than 65 at diagnosis. Rheumatology. 2010;49:1112-1117
  31. 31. Alamanos Y, Tsifetaki N, Voulgari PV, Siozos C, Tsamandouraki K, Alexiou GA et al. Epidemiology of systemic sclerosis in Northwest Greece 1981 to 2002. Seminars in Arthritis and Rheumatism. 2005;34:714-720
  32. 32. Nihtyanova SI, Tang EC, Coghlan JG, Wells AU, Black CM. Improved survival in systemic sclerosis is associated with better ascertaiment of internal organ disease: A retrospective cohort study. QJM. 2010;103(2):109-115
  33. 33. Joven BE, Almodovar R, Carmona L, Carreira PE. Survival, causes of death and risk factors associated with mortality in Spanish systemic sclerosis patients: Results from a single University Hospital. Seminars in Arthritis and Rheumatism. 2010;39(4):285-293
  34. 34. Ruangjutipopan S, Kasitanon N, Louthrenoo W, Sukitawut W, Wichainun R. Causes of death and poor survival prognostic factors in Thai patients with systemic sclerosis. Journal of the Medical Association of Thailand. 2002;85(11):1204-1209
  35. 35. Czirják L, Kumánovics G, Varjú C, Nagy Z, Pákozdi A, Szekanecz Z et al. Survival and causes of death in 366 Hungarian patients with systemic sclerosis. Annals of Rheumatic Diseases. 2008;67:59-63
  36. 36. Arias-Núñez MC, Llorca J, Vázquez-Rodríguez TR, Gómez-Acebo I, Miranda-Filloy JA, Martin J et al. Systemic sclerosis in northwestern Spain. Medicine. 2008;5:272-280
  37. 37. Alba MA, Velasco C, Simeón CP, Fonollosa V, Trapiella L, Egurbide MV et al. Differences in clinical presentation and outcome between early versus late onset systemic sclerosis: analysis of 1037 patients. Medicine (Baltimore). 2014;93(2):73-81
  38. 38. Al-Dhaher FF, Pope JE, Ouimet JM. Determinants of morbidity and mortality of systemic sclerosis in Canada. Seminars in Arthritis and Rheumatism. 2010;39(4):269-277
  39. 39. Sampaio-Barros PD, Bortoluzzo AB, Marangoni RG, Rocha LF, Del Rio APT, Samara AM et al. Survival, causes of death and prognostic factors in systemic sclerosis: Analysis of 947 Brazilian patients. The Journal of Rheumatology. 2012;39(10):1971-1978
  40. 40. Hoffmann-Vold A, Molberg O, Midtvedt O, Garen T, Gran JT. Survival and causes of death in an unselected and complete cohort of Norwegian patients with systemic sclerosis. The Journal of Rheumatology. 2013;40(7):1127-1133
  41. 41. Vettori S, Cuomo G, Abignano G, Iudici M, Valentini G. Survival and death causes in 251 systemic sclerosis patients from a single Italian centre. Reumatismo. 2010;62(3):202-209
  42. 42. Kuo CF, See LC, Yu KH, Chou IJ, Tseng WY, Chang HC et al. Epidemiology and mortality of systemic sclerosis: A nationwide population study in Taiwan. Scandinavian Journal of Rheumatology. 2011;40(5):373-378
  43. 43. Rubio-Rivas M, Royo C, Simeón CP, Corbella X, Fonollosa V. Mortality and survival in systemic sclerosis: Systematic review and meta-analysis. Seminars in Arthritis and Rheumatism. 2014;44:208-219
  44. 44. Ioannidis J, Vlachoyiannopoulos P, Haidich AB, Medsger TA, Lucas M, Michet CJ et al. Mortality in systemic sclerosis: An international meta-analysis of individual patient data. American Journal of Medicine. 2005;118:2-10
  45. 45. Elhai M, Meune C, Avouac J, Kahan A, Allanore Y. Trends in mortality in patients with systemic sclerosis over 40 years: A systematic review and meta-analysis of cohort studies. Rheumatology. 2012;51:1017-1026
  46. 46. Toledano E, Candelas G, Rosales Z, Martínez Prada C, León L, Abásolo L et al. A meta-analysis of mortality in rheumatic diseases. Reumatologia Clinica. 2012;8(6):334-341
  47. 47. Komócsi A, Vorobcsuk A, Faludi R, Pintér T, Lenkey Z, Költo G, et al. The impact of cardiopulmonary manifestations on the mortality of SSc: A systematic review and meta-analysis of observational studies. Rheumatology. 2012;51:1027-1036
  48. 48. Abu-Shakra M, Lee P. Mortality in systemic sclerosis. A comparison with the general population. Journal of Rheumatology. 1995;22(11):2100-2102
  49. 49. Walsh SJ, Fenster JR. Geographical clustering of mortality from systemic sclerosis in the southeastern United States 1981-1990. The Journal of Rheumatology. 1997;24(12):2348-2352
  50. 50. Scussel-Lonzetti L, Joyal F, Raynauld JP, Roussin A, Rich E, Goulet JR, et al. Predicting mortality in systemic sclerosis. Analysis of a cohort of 309 french Canadian patients with emphasis on features at diagnosis as predictive factors for survival. Medicine. 2002;81:154-167
  51. 51. Hissaria P, Lester S, Hakendorf P, Woodman R, Patterson K, Hill C, et al. Survival in scleroderma: Results from the population-based South Australian Register. Internal Medicine Journal. 2011;41:381-390
  52. 52. Mok CC, Kwok CL, Ho LY, Chan PT, Yip SF. Life expectancy, standardized mortality ratios, and causes of death in six rheumatic diseases in Hong Kong, China. Arthritis & Rheumatology. 2011;63:1182-1189
  53. 53. Strickland G, Pauling J, Cavill C, Shaddick G, McHugh N. Mortality in systemic sclerosis-a single centre study from the UK. Clinical Rheumatology. 2013;32:1533-1539
  54. 54. Rubio-Rivas M. Changes in the pattern of death from the Spanish Scleroderma Network [doctoral thesis]. Barcelona Autonomous University UAB; 2014
  55. 55. Rubio-Rivas M et al. Changes in the pattern of death of 987 patients with Systemic Sclerosis from 1990 to 2009 (from the nationwide Spanish Scleroderma Registry). Clin Exp Rheumatol. 2017 Feb 6. [Epub ahead of print]
  56. 56. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Annals of the Rheumatic Diseases. 2007;66:940-944
  57. 57. Geirsson AJ, Wollheim FA, Akesson A. Disease severity of 100 patients with systemic sclerosis over a period of 14 years: Using a modified Medsger scale. Annals of the Rheumatic Diseases. 2001;60:1117-1122
  58. 58. Bond C, Pile KD, McNeil JD, Ahern MJ, Smith MD, Cleland LG et al. South Australian scleroderma register: Analysis of deceased patients. Pathology. 1998;30(4):386-390
  59. 59. Vlachoyiannopoulos PG, Dafni UG, Pakas I, Spyropoulou-Vlachou M, Stavropoulos-Giokas C, Moutsopoulos HM. Systemic scleroderma in Greece: Low mortality and strong linkage with HLA-DRB1*1104 allele. Annals of the Rheumatic Diseases. 2000;59:359-367
  60. 60. Derk CT, Huaman G, Littlejohn J, Otieno F, Jiménez S. Predictors of early mortality in Systemic Sclerosis: A case-control study comparing early versus late mortality in Systemic Sclerosis. Rheumatology International. 2012;32:3841-3844
  61. 61. Assassi S, Junco D, Sutter K, McNearney T, Reveille JD, Karnavas A et al. Clinical and genetic factors predictive of mortality in early systemic sclerosis. Arthritis Rheumatology. 2009;61(10):1403-1411
  62. 62. Hachulla E, Carpentier P, Gressin V, Diot E, Allanore Y, Sibilia J, et al. Risk factors for death and the 3-year survival of patients with systemic sclerosis: The French ItinérAIR-Sclérodermie study. Rheumatology. 2009;48:304-308
  63. 63. Sobanski V, Launay D, Hachulla E, Humbert M. Current approaches to the treatment of systemic-sclerosis-associated pulmonary arterial hypertension (SSc-PAH). Current Rheumatology Reports. 2016;18:10
  64. 64. Giacomelli R, Liakouli V, Berardicurti O, Ruscitti P, Di Benedetto P, Carubbi F, Guggino G, Di Bartolomeo S, Ciccia F, Triolo G, Cipriani P. Interstitial lung disease in systemic sclerosis: current and future treatment. Rheumatology International. 2017. DOI: 10.1007/s00296-016-3636-7. Epub ahead of print
  65. 65. Woodworth TG, Suliman YA, Furst DE, Clements P. Scleroderma renal crisis and renal involvement in systemic sclerosis. Nature Reviews Nephrology. 2016;12:678-691
  66. 66. Fernández-Codina A, Simeón-Aznar CP, Pinal-Fernandez I, Rodríguez-Palomares J, Pizzi MN, Hidalgo CE, Del Castillo AG, Prado-Galbarro FJ, Sarria-Santamera A, Fonollosa-Plà V, Vilardell-Tarrés M. Cardiac involvement in systemic sclerosis: Differences between clinical subsets and influence on survival. Rheumatology International. 2017;37:75-84
  67. 67. Savarino E, Furnari M, De Bortoli N, Martinucci I, Bodini G, Ghio M, Savarino V. Gastrointestinal involvement in systemic sclerosis. La Presse Medicale. 2014;43(10 Pt 2):e279-291
  68. 68. Onishi A, Sugiyama D, Kumagai S. Cancer incidence in systemic sclerosis: meta-analysis of population-based cohort studies. Arthritis & Rheumatology. 2013;65(7):1913-1921
  69. 69. Moinzadeh P, Fonseca C, Hellmich M, Shah AA, Chighizola C, Denton CP, Ong VH. Association of anti-RNA polymerase III autoantibodies and cancer in scleroderma. Arthritis Research and Therapy. 2014;16:R53
  70. 70. Juárez M, Misischia R, Alarcón GS. Infections in systemic connective tissue diseases: Systemic lupus erythematosus, scleroderma, and polymyositis/dermatomyositis. Rheumatic Disease Clinics of North America. 2003;29:163-184
  71. 71. Nandi S, Santra A, Ghoshal L, Kundu S. Interstitial lung disease in systemic scleroderma, complicated with bilateral pulmonary aspergilloma: An unusual association. Journal of Clinical and Diagnostic Research. 2015;9:OD11-3. DOI: 10.7860/JCDR/2015/15340.6926
  72. 72. Au K, Singh MK, Bodukam V, Bae S, Maranian P, Ogawa R, Spiegel B, McMahon M, Hahn B, Khanna D. Atherosclerosis in systemic sclerosis: A systematic review and meta-analysis. Arthritis & Rheumatology. 2011;63:2078-2090

Written By

Manuel Rubio-Rivas

Submitted: May 17th, 2016 Reviewed: March 14th, 2017 Published: October 4th, 2017