Systemic Sclerosis

Introduction Systemic sclerosis (SSc) is a connective tissue disease clinically characterized by different degrees of skin fibrosis and visceral organ involvement (17,19,22). The etiology of SSc remains obscure; the disease appears to be the result of a multistep and multifactorial process, including immune system alterations, genetic and exogenous, and toxic or infectious factors (17,19,22). The epidemiology of SSc is not definitely established due to the relative rarity of the disease, the difficulty in diagnosis, and its extreme clinical variability. SSc affects females more frequently than males, with a peak of incidence between ages 45 and 64 years (19,22). There seems to be an increased incidence of the disease in blacks, particularly in black females, but no other significant racial differences in distribution. Various HLA studies in SSc patients failed to identify any clearcut associations, even if a role of specific HLA antigens might be hypothesized for particular clinico-serologic SSc subsets (19). Moreover, familial factors are certainly important for SSc development: it is not rare to observe a scleroderma patient with 1 or more firstdegree relatives with another autoimmune systemic disorder, such as Raynaud phenomenon, systemic lupus, or rheumatoid arthritis (19,22). The annual incidence (new cases/population at risk per year) of SSc varies largely among different surveys (from 0.6 to 19.1 per million/year), as does the estimated prevalence (number of cases living at a particular time or during a given time interval per million of population at risk: from 126 to 1,500). The actual incidence and prevalence of the disease are generally underestimated; the minimum estimated values are 20/million per year and 1,500/million, respectively. The number of undiagnosed cases, especially in the oldest surveys, might be significant; this is due, at least in part, to the clinical characteristics of the disease. SSc includes a wide spectrum of symptoms, varying from very mild cutaneous and internal organ involvement to diffuse fibrosis responsible for organ failure (4,11,17,19,22). A variable combination of organ damage, or, less frequently, a severe, single organ involvement, is responsible for SSc morbidity and mortality. Among different connective tissue diseases, SSc shows the poorest prognosis (17,19,22). The availability of well-recognized criteria for diagnosis, disease activity (34), and severity (21), as well as of valuable prognostic parameters, should be decisive for timely patient identification, clinical assessment, and management. In the absence of valuable diagnostic criteria, patients are usually classified according to the American College of Rheumatology (formerly ARA) preliminary criteria for SSc classification (32) (Table 1). The introduction of capillaroscopic SSc pattern (capillary dilation with or without capillary dropouts) and SSc-related serum autoantibodies might improve the usefulness of classification criteria, particularly in discriminating the early stage of the disease. However, these criteria are not intended to assist in the diagnosis of individual patients, which is based on the careful observation of different clinical and laboratory features.TABLE 1: Classification criteria and diagnostic parameters of systemic sclerosis (SSc)Diagnosis of SSc in patients with diffuse cutaneous sclerosis is quite easy; on the contrary, it can be particularly difficult during the early stage of the disease or in the presence of sine scleroderma SSc (ssSSc) (Figure 1). In these instances, isolated Raynaud phenomenon (Table 2) or other connective tissue diseases must be ruled out. Diagnosis of SSc is currently based on the presence of cutaneous manifestations (symmetrical, truncal, and/or acral skin sclerosis, skin ulcers, digital pitting scars, telangiectasias, calcinosis), typical internal organ involvement (lung fibrosis, esophageal dysfunction, heart and/or renal alterations), capillaroscopic scleroderma pattern, and autoantibody profile (see Table 1, Figures 1–3).TABLE 2: Approach to apparently isolated Raynaud phenomenonFig. 1: Systemic sclerosis (SSc) classification according to skin sclerosis extent (black areas). Sine scleroderma SSc (ssSSc): absence of cutaneous sclerosis in patients with typical SSc visceral organ involvement, capillaroscopic changes, and serum autoantibodies. Limited cutaneous scleroderma (lcSSc): skin sclerosis of fingers (sclerodactyly) with or without mild sclerotic lesions at neck, face, and armpits. Intermediate cutaneous scleroderma (icSSc): sclerosis of upper and lower limbs, neck and face, without truncal involvement. Diffuse cutaneous scleroderma (dcSSc): distal and truncal skin sclerosis.Fig. 2: Capillaroscopic findings. a. Normal subject. b. Patient with isolated Raynaud phenomenon. c. and d. Typical scleroderma patterns:c. diffuse capillary enlargement (megacapillaries), d. presence of megacapillaries and large avascular areas (capillary dropouts).Fig. 3: Cutaneous manifestations of SSc. A. Patient with limited cutaneous SSc (lcSSc): mild perioral sclerosis and diffuse telangiectasias. B. Patient with diffuse cutaneous SSc: marked skin sclerosis at face and neck, diffuse hypermelanosis with some hypochromic areas. C. Digital pitting scars and pulp ulcers in lcSSc. D. Subcutaneous calcinosis at knees in lcSSc.The large variability in the disease course, generally characterized by progressive, often subclinical, visceral organ deterioration, makes the long-term outcome of SSc extremely unpredictable. The clinical and autoantibody pattern of the disease observed in different patient populations may also vary widely (2,8,10–15,17,19,22,30,31,35). The relationship between clinico-serologic features of SSc and survival rates can give us useful prognostic parameters. Moreover, follow-up studies on different patient series can yield new insights on the possible variations of SSc pathomorphism during the last few decades. These changes could be the consequence of different racial and etiopathogenetic factors, as well as of improved therapeutic strategies. In this light, we retrospectively investigated demographic and clinico-serologic features in a large cohort of Italian patients with SSc, and their relationship to survival. Patients and Methods In 1997 the Italian Society of Rheumatology (SIR) promoted the present study involving 3 University-based divisions of rheumatology from the north (University of Padova), center (University of Pisa), and south (University of Napoli) of Italy with comparable, long-term experience in SSc patient management. Patients The study population was recruited between 1955 and 1999 at the 3 participating centers. One thousand twelve patients (897 females, 115 males; mean age at presentation, 50.5 ± 13.8 SD years; see Table 3) were included in the study; namely, 323 patients from Padova were collected between 1978 and 1999, 349 from Pisa between 1972 and 1999, and 340 from Napoli between 1955 and 1999.TABLE 3: Clinico-epidermiologic features of 1,012 Italian patients with SSc*At the beginning of the follow-up, corresponding to the time of diagnosis, all patients fulfilled the American College of Rheumatology (formerly ARA) criteria for SSc classification (32; see Table 1). At the same time, patients were also classified based on the extent of skin sclerosis according to the 3-cutaneous subset model (18). These subsets are 1) limited cutaneous scleroderma (lcSSc): sclerosis of fingers with or without sclerosis of the neck and/or face; 2) intermediate cutaneous scleroderma (icSSc): sclerosis of upper and lower limbs, neck, and face, without truncal involvement; and 3) diffuse cutaneous scleroderma (dcSSc): distal and truncal skin sclerosis (see Figure 1). For the survival study patients were also grouped according to the 2-cutaneous subset classification (17,19,22,31); namely, patients were classified as having limited cutaneous scleroderma (sclerosis of distal extremities, not above the elbow and knees, with or without sclerosis of neck and face) or diffuse cutaneous scleroderma (sclerosis of both distal and proximal extremities, with or without truncal involvement). Patients with ssSSc were invariably included in the lcSSc subset (12,26). Clinical assessment Epidemiologic and clinico-serologic assessment was carried out at different centers using data from patient records in 3 main categories: demographic data and symptoms at SSc onset, clinical features observed at the time of referral, and cumulative clinical manifestations observed during the entire follow-up. Standardized criteria were followed for the evaluation of clinical symptoms (11,12). In particular, the age at disease onset was considered to be the age at which the first signs and symptoms compatible with the disease appeared; namely, Raynaud with digital ischemic lesions, puffy hands, sclerodactyly with or without proximal scleroderma, dyspnea, and/or dysphagia. Organ involvement was evaluated according to the criteria previously described (11,12) with some modifications. In particular, each type of involvement was defined as follows: 1) peripheral vascular: Raynaud phenomenon with digital pitting scars (see Figure 3) and/or ulcerations or gangrene; 2) joint: presence of polyarthralgia or arthritis when inflammatory changes were observed in more than 2 joints; 3) muscle: isolated muscle weakness or weakness associated with elevated serum creatine kinase with or without electromyographic or histologic changes of inflammatory myopathy; 4) esophageal: dysphagia and or esophageal radiographic dysmotility; 5) pulmonary: bibasilar fibrosis at standard chest X-ray and/or restrictive lung disease on pulmonary function tests and/or pulmonary hypertension; 6) cardiac: at least 1 of the following symptoms: pericarditis, congestive heart failure, severe arrhythmias, and/or atrioventricular conduction abnormalities; 7) renal: scleroderma renal crisis with increased diastolic blood pressure and/or progressive renal failure. Laboratory findings At the beginning and/or during the follow-up, the presence of serum autoantibodies was investigated in 755 SSc patients by means of standard techniques (11,12): antinuclear (ANA) and anti-nucleolar antibodies (ANoA) by indirect immunofluorescence on rat liver (dilution 1:20) and/or on Hep-2 cell lines (dilution 1:40); anticentromere antibodies (ACA); antiextractable nuclear antigen (ENA) antibodies, including anti-Scl70, -Sm, -RNP, -SSA/SSB. Routine blood chemistry and urinalysis were also performed at the first visit and at regular time intervals during follow-up. Survival rates During 1999 the vital status of all patients lost to follow-up was established by contacting the patients themselves or relatives, their primary care physician, or the municipal death registry. For patients known to have died, hospital records, autopsy reports, or death certificates were examined, when possible, to establish the date and cause of death. On the whole, 90.4% of patient accountability was determined at the end of the study. For those patients with ascertained cause of death, each death was classified as definitely SSc-related (death caused by organ insufficiency, such as renal crisis, or by a manifestation attributable to no other causes or predisposing than SSc, for severe lung SSc-related (death caused by a manifestation by SSc-related organ involvement, such as severe lung fibrosis, or with increased in SSc, for lung and to SSc organ or survival rates were by the and the between survival by the using Survival were to in the and Italian population from Italian identify important prognostic the individual of some on survival was evaluated with the of the model using to a process, were or from the on the of a by model and were also performed for each of the the relationship to risk of main skin and and parameters anti-Scl70, and The for each variable was as the of the of the variable in the Moreover, between were using the with the The with the was for A was considered and clinical features of 1,012 Italian patients evaluated at the beginning and at the end of follow-up ± are in Table At the last patients were were known to have died, and were considered lost to follow-up. These the same clinico-serologic characteristics of the patients evaluated for survival study. The from of the entire SSc population at first visit to of the At the time of diagnosis lcSSc was the cutaneous its prevalence was more at the end of follow-up the prevalence of clinical features to both living and patients with the of and renal involvement; arthritis was less frequently Table shows the of the main features among different SSc cutaneous subsets at A of patients was observed in both and than lcSSc disease from SSc onset was with the extent of skin sclerosis In and clinical manifestations were more particular, skin ulcers, and esophageal and lung involvement (see Table was more associated with lcSSc. The prevalence of clinical symptoms observed in and was by the observed in the same subsets to lcSSc Cutaneous SSc subsets and features at autoantibodies were evaluated during the last 2 in of patients the prevalence of anti-Scl70, and in the SSc series and their with clinical features are in Table At least 1 and/or and/or was in of and were with the of both autoantibodies in the same serum On the contrary, of patients also serum or was among 3 patient were in females and in and were more in and In the presence of main organ involvement not with serum calcinosis and were more in and hypermelanosis in is the number of patients was lower in to or between SSc-related autoantibodies and of death were definitely ascertained in of patients (Table A of was observed in than in females and lung involvement, or in were the the disease important but less causes of death were and severe renal of rates At the first clinical evaluation the 3 SSc series a with to patient mean and cutaneous However, different year survival rates were observed among the 3 patient cumulative were observed in SSc series with to the year of beginning of the in particular, the Napoli series Pisa and Padova for patients recruited these differences were less and The of the survival study are in Table survival of the SSc series of 1,012 patients (Figure from the time of diagnosis, an with rates of and at the and respectively. The observed survival rates were lower than those in the Italian and population from disease onset, a survival was see Table Survival from disease onset was also in those patients with disease recruited In this particular the survival from disease onset was to observed from diagnosis in the SSc series see Table and Figure The prognostic of patient age at the time of disease onset was evaluated by survival rates in 3 of patients from to and The observed among these were and lower than those in and from the Italian population Moreover, patients a prognosis than females both and SSc patients a lower survival to the corresponding from the The extent of cutaneous sclerosis was with survival Moreover, the survival of was from both the lcSSc and subsets (Figure the 2-cutaneous subset different survival rates were observed for lcSSc and Survival rates in different patient at and year and from diagnosis in 1,012 SSc patients to survival in the Italian population survival rates in patients recruited during and Survival rates in and patients were lower than survival rates Survival rates in cutaneous SSc subsets classified according to the model and diffuse or the model intermediate and diffuse patients with Raynaud or at the time of disease onset, different survival rates from diagnosis were observed The presence of main organ involvement and was associated with lower survival the survival was observed for patients with renal involvement and for a of patients with and involvement (Figure see Table significant differences were observed in SSc subsets classified according to of serum or patients were characterized by a prognosis with patients (Figure see Table Survival rates in different visceral organ involvement The presence of visceral organ involvement was associated with survival rates with the absence see also Table Survival rates in patients with or without serum autoantibodies of and survival by model (Table some of the above prognostic findings by survival main skin and in a large of SSc patients were frequently were not in this were associated with increased risk of at often by In particular, by means of for in year of age was a in an and involvement a and respectively. cutaneous subsets an increased which was to the extent of skin in the of was 3 observed in lcSSc. The of patients, including parameters, increased at diagnosis was associated with the presence of serum was associated with a lower risk (see Table between SSc and risk factors by and the survival study on the possible variations of SSc outcome during the last few in this survival rates were evaluated by the SSc series in 2 according to different time intervals of In particular, patients recruited from to 1999 a survival with those recruited from 1955 to (Figure see Table The survival observed in the present SSc population was to the mean of survival rates in other SSc series during the last In this the mean survival observed in the was lower than in more studies (see Table Survival studies in systemic sclerosis follow-up study evaluated and prognostic parameters in a large Italian SSc patient A number of demographic and clinical features in the of In particular, the disease more frequently affects limited cutaneous involvement the clinical and SSc involvement shows a significant follow-up. The prevalence of features such as and esophageal involvement was increased at the last patient a outcome was in of SSc could be or responsible for death in the of involvement and were the causes of death, severe renal involvement was observed in a number of The prevalence of in SSc patients and its relative among causes of death are to other series from or the a prevalence of renal involvement was in other patient series from the other genetic and/or the in the prevalence of renal involvement among SSc patient populations might be to different for the of this Survival study a in SSc patients to the Italian the of patients an during a follow-up The prognostic parameters were the a wide extent of skin sclerosis, and the presence of main visceral organ involvement, and useful prognostic was the time interval between the of Raynaud phenomenon and the onset of a Raynaud at the disease onset with a survival. to the a relationship between the presence of or and the extent of skin sclerosis was namely, were more in and in both and the survival study a role of as observed in a prognosis was in On the contrary, patients with and/or a of to The by model the prognostic of the above parameters. increased risk was with extent of skin sclerosis, presence of and renal involvement; findings have in other patient series from the and the However, some important differences with to the prevalence of clinico-serologic features and survival rates among series from different as well as between the present SSc series and studies see Table is often difficult to these racial and/or etiopathogenetic factors, and not different among centers should be There is to the extent of skin sclerosis as the useful In the absence of other more specific and clinico-serologic parameters, the SSc classification in cutaneous subsets a and useful particularly at the patient The present study observation a discriminating of the classification (11,12). In patients with corresponding to a lower with a survival to patients with or These 2 subsets a number of clinico-serologic the prevalence of skin ulcers, esophageal and lung involvement, and with the of On the contrary, the presence of with or without sclerosis of the neck and/or face, seems to identify a of patients with the For clinical a classification of SSc patients should be by different centers. the or it might be to with very limited skin sclerosis (sclerodactyly) in a subset with clinico-serologic and prognostic with other connective tissue diseases, SSc is characterized by a The outcome may be the consequence of severe single organ or or more often it may be the result of the involvement of internal a single clinical even the extent of cutaneous sclerosis, is not a prognostic in a given In this survival studies on large SSc series can give us new insights on the prognostic of different clinico-serologic parameters. However, have out the in survival data from different patient populations of their The to survival studies is of to be the of patient and the survival SSc is a rare disorder, characterized by a wide spectrum of clinical very mild to clinical are is the more severe cases are in the actual from scleroderma, evaluated in patients may be In the evaluation of the of the disease the of the disease from disease onset to death. However, this could be is a between the clinical onset and the diagnosis, especially for progressive SSc in these cases it is often to a date for the disease onset, even for the patients Moreover, this an important the patients to centers not the entire SSc but a the survival from disease onset invariably the from SSc. In an number of patients with early SSc have to Italian centers due to the of the disease by and patients as well as the wide of some diagnostic such as In the studies on patient populations early in the of the disease could the In the present study we have to these at least in part, by the survival in those patients with early SSc to the 3 Italian centers particular of patients, date of disease onset was could the actual of the SSc the survival from disease onset in this was to from diagnosis in the SSc series is difficult to the of this One possible could be cumulative SSc survival from diagnosis is with 2 the in centers of a population with more severe disease and on the 1 and the presence of a SSc cohort with on the other to the above factors, the survival rates from diagnosis, as usually in might the actual outcome of the disease. survival rates observed in 3 patient series a A possible role of genetic and/or in different series can be on the of the following to the Padova patients in the Pisa and especially the Napoli series recruited a time including the and when a of patients with more severe SSc were to centers. evaluated in patients to the 3 centers survival rates were among the 3 SSc more severe SSc were in centers during the last decades. could be by the survival rates observed in more studies with The improved prognosis among SSc patient populations seems to be of different racial and/or and/or different is possible to the improved SSc largely observed during the last could be to a patient at which the entire scleroderma Moreover, the possible of also should be The of SSc is 2 of organ scleroderma renal crisis, lung or heart involvement, and digital and at the (Table the present of any or combination of as some significant have in the last years in manifestations In this some studies have out the of in the of in its early inflammatory The extreme variability of SSc us from a useful for all the must be to the individual patient on the extent and severity of organ involvement and the stage of the disease, or of systemic In this study we the and prognostic features of a large Italian systemic sclerosis (SSc) series patients, females and 115 males; mean age at presentation, 50.5 ± 13.8 mean follow-up, ± recruited between 1955 and 1999 at 3 rheumatology from the north (University of Padova), center (University of Pisa), and south (University of Napoli) of Limited cutaneous SSc was the subset with the prognosis of the classification based on skin sclerosis extent or The of organ involvement increased at the last patient The of the disease during follow-up was by the in the cumulative survival rates at the and year from diagnosis and the observed SSc survival rates were lower than those in the Italian population Among SSc patients, prognosis was observed in the diffuse cutaneous subset in and in patients with lung heart and renal involvement A of Raynaud phenomenon the scleroderma onset was with outcome to the presence or absence of was an important prognostic and by model the of survival the risk was increased in in patients with diffuse cutaneous in patients with and involvement; and in patients with evaluated at patient of patients during the follow-up the causes of death were and lung involvement, and were definitely or to SSc in and of cases, respectively. involvement was a rare in Italian SSc features were observed in other SSc populations from the Patients recruited a survival with survival rates have in studies on SSc series from other could be to the of clinical at which the entire scleroderma not to the possible of