Scleroderma-like diseases

A fairly strong and consistent association between exposure, primarily in occupational settings, to solvents (e.g. trichloroethylene) and scleroderma has been reported in numerous epidemiological studies (see chapter 8). Scleroderma-like diseases can also be induced by other chemical compounds, such as drugs (D Cruz, 2000) and silica ( Erasmus syndrome ). Workers exposed to vinyl chloride monomers exhibit clinical features that resemble systemic sclerosis, such as fibrotic skin lesions, pulmonary fibrosis, and skin capillary abnormalities. However, vinyl chloride disease also harbours several features that are clearly distinct from systemic sclerosis. After exposure is discontinued, skin lesions, capillary abnormalities, and acroosteolytic lesions revert to nearly normal (Haustein Ziegler, 1985). 

SSc, characterized by fibrosis of the skin and internal organs, is a disease of unknown etiology with a pathogenesis that is still vague. The prevalence in a Caucasian population is estimated at 0.3-1.9 per 100,000 (Haustein and Albrecht 1993). Women are affected three to six times more frequently (Medsger and Masi 1971 Sluis-Cremer et al. 1985). In recent years, some environmental substances have been reported as inducing factors in SSc and in so-called scleroderma-like diseases (SLD) (Table 1). 

Table 10. Cases of systemic sclerosis (SSc) and scleroderma-like diseases (SLD) in association with exposure to solvents...

Connective tissue disorders such as SSc, LE, Sjogren s syndrome, dermatomyositis and RA can be induced by occupational exposure to silica, solvents, and other chemical offenders. An enhanced genetic susceptibility seems to favor these disorders. SSc is the most frequent and best-studied disease. While silica precipitates SSc, the other offenders induce scleroderma-like diseases with different clinical and laboratory findings than with SSc. Taking a careful case history of patients with SSc will help to identify the occupational causes. The best way to prevent this type of connective tissue disease is to minimize the exposure to occupational substances. However, efforts in the form of individual expert decisions have to be made in order to acknowledge these disorders as occupational diseases and provide some social and financial support to patients and reduce the harm caused by these disorders. 

For some patients, cessation of tryptophan ingestion led to resolution of the symptoms in other patients the use of high dose corticosteroids appeared to be helpful. However, for some patients, the disease evolved into a chronic phase, with cutaneous, neuromuscular, pulmonary, cardiac, and cognitive involvement. The most common features of chronic EMS are fatigue, muscle cramping, myalgia, paraesthesias with objectively demonstrated hypes-thesias (lessened sensitivity to touch), chronic joint pain, scleroderma-like skin changes, and proximal muscle weakness. In one study, 88% of EMS patients continued to manifest more than three of these clinical symptoms after 3 years. 

The most common objective clinical components of the chronic phase of EMS involve the skin, muscle, and nerves.33 Several reports have focused attention on long-term follow-up studies of EMS.34 36 Most of the patients continued to have symptomatic disease with the following clinical manifestations fatigue, myalgia, paresthesias, articular symptoms, scleroderma-like skin changes, and muscle weakness.35 Cognitive symptoms were new findings that were observed frequently.35-37 38... 

It is notable that cadmium as well as mercury and gold can initiate or aggravate autoimmune manifestations in normal or autoimmune-prone animals, respectively. It would seem likely that these heavy metals have the same effects on humans, presumably by a similar mechanism. Autoimmune manifestations induced by heavy metals include lupus-type nephritis, autoimmune haemolytic anaemia, and skin diseases, such as pemphigus and scleroderma-like lesion. Some manifestations of immune-mediated nephritis and elevation of circulating autoantibodies have been noted in case-studies of persons exposed to gold and cadmium as well as mercury (Ohsawa, 1993 Bigazzi, 1994, 1999). 

In addition, silicone-containing medical devices, particularly breast prostheses, have been reported to cause serum-sickness-like reactions, scleroderma-like lesions, and an SLE-like disease termed human adjuvant disease [11,23]. Some patients may also present with granulomas and autoantibodies. Human adjuvant disease is a coimective tissue or autoimmune disease similar to that of adjuvant arthritis in rats and rheumatoid arthritis in humans. Autoimmime disease-like symptoms usually develop 2-5 y after implantation in a small percentage of people that receive implants, which may indicate that there is a genetic predisposition similar to that for... 

Solvents have been reported as predisposing or eliciting factors in some patients with scleroderma-like reaction. The reaction is suspected to result from repeated cutaneous contact with the solvent. The pathogenic mechanism is unknown. Walder (1983) reported six scleroderma patients who had close contact with aromatic hydrocarbon solvents, such as benzene, toluene and white spirit. Unlike chlorinated hydrocarbons, these aromatic hydrocarbons do not produce multisystem disease resembling vinyl chloride disease. The associated scleroderma is limited to the skin of hands and feet where the direct contact took place. 

The first large study was conducted in Rumania in 1963, where 168 PVC workers had been observed over 4 years (Suciu et al. 1963). The symptoms included pruritus of the arms and face, and scleroderma-like lesions which mostly disappeared after removal from the workplace. Later on, the disease was described in detail and labeled as occupational acro-osteolysis (OAOL) in England, France, and the USA (Cordier et al. 1966 Harris and Adams 1967 Wilson et al. 1967 Dinman et al. 1971 Markowitz et al. 1972). The disease is characterized by Raynaud s phenomenon, papular-fibrotic skin lesions on the wrist and dorsa of the hands, and osteolysis in the middle of the distal phalanges (bullet holes), mainly of the first three fingers, which became shortened and shapeless. OAOL occurred only in those workers who had been exposed to the VC monomer and was most common in reactor cleaners (Lelbach and Marsteller 1981). 

Purpuric allergic contact dermatitis, scleroderma-like disorders, atypical psoriasis and erythema multiforme have been described to be caused by exposure to epoxy compounds (Holness and Nethercott 1989) Bach-urzewska and Borucka (1986) reported Raynaud s-disease-type ailments. Rycroft (1980) reported on a patient whose epoxy-resin sensitisation was followed by atypical psoriasis, while Lichter et al. (1992) described a patient whose sensitisation to epoxy resin and hardener was followed by lichenoid contact dermatitis. Photosensitivity has been reported in relation to the heating of DGEBA epoxy resin and the use of epoxy powder paints (Goransson et al. 1984). Photosensitivity is considered probably to be due to bisphenol A contained in the resin (Maguire 1988). 

ILD in SLE may occur as a residual feature of acute lupus pneumonitis (278,288) or may present insidiously, often with mild flares of pulmonary activity (277,293,309). The symptoms are nonspecific with persistent dyspnea on exertion, occasional pleuritic chest pain, and non-productive cough. Physical examination may reveal fever, cyanosis, or bibasilar crackles. Clubbing is less common in SLE-ILD than in IPE (310). The pattern and severity of PFT impairment do not correlate with systemic disease activity, as judged by anti-DNA antibodies and serum complement levels (293,311,312). ELD can occur in the absence of active disease in other organs (282,312). Interestingly, the presence of scleroderma-like traits in SLE is associated with a higher prevalence of restrictive defects or reduced DLco (313). Progressive severe ELD rarely complicates SLE but is seen in some patients with SLE features as part of an overlap syndrome (314). 

Antinuclear antibodies were found in 14 of 70 children on ethosuximide and/or phenytoin, and in 5 of 23 on phenobarbitone alone. On frequent surveillance, none developed clinical signs of systemic lupus erythematosus. It is probably unnecessary therefore to discontinue the drugs in children with antinuclear antibodies, but careful observation is required. Five children with clinical systemic lupus-like disease were observed. In each case, symptoms appeared within 1 —6 months of starting ethosuximide. The syndrome included fever, malar rash, lymphadenopathy, arthropathy, pleural effusions, myocarditis and pericarditis (43 ). Scleroderma has also been attributed to ethosuximide therapy (51 ). All these cases were on other anticonvulsants as well, but ethosuximide seemed to be the precipitating drug. 

Paradoxically, penicillamine is occasionally involved in the development of rare diseases for which it is also sometimes used, such as systemic sclerosis-like lesions (245) and circumscribed scleroderma (or morphea) (246,247). 

Penicillamine is a chelating agent which binds copper, mercury, zinc, and lead. It has been used to treat poisoning from these chemicals and also for disorders of copper metabolism such as Wilson s disease and primary biliary cirrhosis. Penicillamine has been tried in scleroderma and arthritis. Hypersensitivity reactions are common. About 20%-30% of the patients show hypersensitivity reactions suchs as morbilliform exanthema, urticaria, purpura, anorexia, lymphadenopathy, leukopenia, and thrombocytopenia (Meyboom 1975 Balme and Huskisson 1977). More severe skin symptoms associated with penicillamine therapy are Stevens-Johnson syndrome, pemphigus, myasthenia gravis, cholestatic jaundice (Barzilai et al. 1978), nephropathy (Lange 1978) and lupus-like syndrome (Harpey et al. 1972). 

Colchicine with its microtubule-disrupting properties limits the chemotactic and phagocytic activity of polymorphonuclear lymphocytes. It also induces the release of prostaglandin E, a suppressor of leukocyte function by increasing the level of cyclic adenosine monophosphate [39]. Furthermore, the ability of colchicine in inhibition of IL-1 production and histamine release makes it an excellent drug for a number of dermatitis-related complexities like psoriasis, Behget s syndrome, recurrent aphthous stomatitis, leukocytoclastic vasculitis and urticarial vasculitis, bullous disease, scleroderma, fibromatosis. Sweet s syndrome, amyloidosis, and many more [40]. 

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