Coagulation factor XIII in scleroderma

ARTICLE

More than twenty years ago in Lyon, Thivolet and coworkers were the first to use blood coagulation factor XIII in the treatment of scleroderma. They observed clinical improvement in a significant number of patients who received this blood coagulation factor. The improvement of skin sclerosis was the most consistently observed beneficial effect. Further assessment of the drug's efficacy was made impossible when, following the HIV epidemic, FXIII placental extract was made unavailable. Since then, safer plasmatic extracts have been developed. However, because of the ongoing, strict regulations related to the theoretical viral threat, these extracts cannot be offered to patients with scleroderma in several countries. A recent international congress on scleroderma held in Milan (Systemic sclerosis towards the year 2000, Milan, Italy, October 3-5, 1997) provided an opportunity to review what would be the impact of FXIII therapy on the management of the disease if the regulations were to be widened.

Blood coagulation factor XIII

Blood coagulation factor XIII (FXIII) is a protransglutaminase that becomes activated by the concerted action of thrombin and Ca²⁺ in the final stage of the clotting cascade. The end result of this process is the formation of an active transglutaminase, which cross-links peptide chains through epsilon (gamma-glutamyl) lysyl isopeptide bonds. In addition to plasma, FXIII is also found in platelets, monocytes, and monocyte-derived macrophages. The main physiological function of plasma FXIII is to cross-link fibrin and protect it from the fibrinolytic plasmin. Furthermore, plasma FXIII seems to be involved in wound healing and tissue repair, and it is essential for maintaining pregnancy.

Physiopathologic basis for the use of FXIII in the treatment of scleroderma

FXIII (Fibrogammin HS^®) was proposed for the treatment of scleroderma more than twenty years ago, following the observation that this transglutaminase was able to polymerize collagen fibers as it does for fibrin molecules in the blood coagulation process [1]. At that time, it was thought that stabilization/immobilization of soluble collagen molecules, which are produced in abnormally high amounts in the disease, might be beneficial in some way [2]. Although a beneficial effect was indeed observed, the ability for FXIII to modify the distribution between soluble and insoluble collagen was never confirmed, at least in vitro [3]. Fibronectin is another macromolecule which accumulates in the affected organs during scleroderma. Because FXIII is also able to cross-link collagen to fibronectin [4], it was hypothesized that this event might promote the removal and degradation of both types of fiber by cells of the reticulo-endothelial system which could explain the drug's activity [5, 6]. FXIII's ability to modulate fibroblast function might also account for the observed therapeutic effect. Indeed, this blood coagulation factor can clearly interact with fibroblasts [7] and was shown to inhibit collagen synthesis and increase collagen degradation activity [3]. However, these data remain controversial [8, 9] and FXIII has been shown to favor fibroblast proliferation [10]. Recently, evidence was obtained which suggested that FXIII might play a role in improving endothelial damage, a early pathogenic event in systemic scleroderma. Indeed, measuring plasma levels of von Willebrand factor (vWF), a marker of endothelial cell injury, Marzano A.V. and coworkers observed that while vWF levels were increased in patients who did not received FXIII, in the treated patients, levels of vWF were close to normal (Marzano A.V., personal communication). Finally, there is no direct relationship between FXIII deficiency and scleroderma since patients who congenitally lack this blood coagulation factor do not experience systemic sclerosis and when measured, FXIII blood levels are always found to be normal in patients with systemic scleroderma. Therefore, even today, the mechanisms underlying the beneficial effect of FXIII in scleroderma remain unclear.

Factor XIII concentrates

Human FXIII concentrate was obtained initially for therapeutic purposes from placenta (Fibrogammin HS^®, Hoechst^™). This concentrate has now been replaced by plasmatic extracts which are safer in terms of the viral threat (FXIII-BLP^®, Bio-product laboratory^™; Fibrogammin P^®, Beringwerke AG^™). Indeed, for plasmatic extracts, blood is obtained from donors screened for hepatitis and HIV infection. FXIII is fractionated from plasma using the Cohn technique and then precipitated with sodium citrate. These fractionation steps are known to participate in the potential elimination of infectious agents [11]. The final product is further pasteurized with sorbitol, a technique which has been shown to inactivate a broad spectrum of viruses, both enveloped and non-enveloped [12]. An even safer product might one day be available since recombinant FXIII has been developed in some laboratories [13].

FXIII availability varies significantly from one country to another. For instance, in France the only concentrate available (FXIII-BLP^®) is imported from Great Britain and its use is strictly restricted to the approximately 20 people in France who lack this blood coagulation factor.

FXIII in scleroderma:
twenty years later, what do we know?

Following the HIV epidemic and because of it being a human-derived product, Fibrogammin HS^® was made unavailable to physicians in France and several ongoing trials had to be stopped. Only a very limited number of studies [2, 3, 5, 14-18], is today available which allow us to precisely delineate the indications, efficiency and optimal regimen of FXIII in scleroderma. Notably, no prospective study is available which might have assessed whether or not FXIII might be helpful for slowing the evolution of the disease in the early stages. Furthermore, apart from one study which assessed short term efficiency of the treatment [5], none of the available studies was double-blinded, randomized, with control or crossover. Nevertheless after two decades, some general trends can be identified regarding FXIII therapy in scleroderma.

Standard treatment course

Based on the half life of FXIII (10 days) [19], the need to discriminate between responders and non-responders and by comparison to other regimens, a standard treatment course has been proposed [14, 20]. It consists of cycles of a three week intensive course followed by a six month maintenance therapy (Fig. 1). During the intensive course, 500 U of FXIII are injected daily. If no improvement is observed after the first intensive course, the treatment is discontinued. The maintenance therapy consist of one injection of 500 U every ten days. The number of cycles administered is based upon clinical assessment. The estimated cost for an intensive course is $5,000 and the six month maintenance therapy will account for another $5,000. As a comparison, the cost for bleeding prophylaxis in people who lack FXIII (60 U/kg/4 weeks) comes close to $2,000/4 weeks. Recently, Marzano [17] suggested that a half dose intensive course (500 U every other day) might be as effective, although he stressed the need to further evaluate this regimen.

FXIII safety

Short and long term drug safety of FXIII in scleroderma has proved to be excellent. Only one alleged side effect has been reported: a bronchiole-alveolar carcinoma complicating systemic scleroderma under long-term treatment [21]. To date, this case remains isolated and the authors did not provide clear evidence for a direct relationship between FXIII therapy and carcinoma onset. In people with congenital deficiencies who usually receive 60 U/kg every 4 weeks, rashes, nausea and headaches have been reported, but no carcinomas. These effects always disappeared rapidly when the rate of perfusion was reduced. As mentioned earlier, the threat of infection is minimized but will theoretically remain until recombinant FXIII becomes available on a therapeutic scale.

Skin sclerosis

Improvement of skin sclerosis as evaluated objectively by the physician or subjectively by the patients is the most consistently if not the only beneficial effect observed. Furthermore, to date, cutaneous improvement is the only effect of this therapy that has been demonstrated [5]. However, it should be emphasized that this was demonstrated in a limited number of patients, 25, and only short term efficacy of the treatment was assessed. Indeed, in this double blind, randomized, cross-over study, patients received FXIII for no more than three weeks and were clinically evaluated for a total of 4 months. Although they were all open studies, larger series were then published which confirmed these data and suggested lasting effects of FXIII therapy on skin involvement. According to these studies, in responders, body surface involvement and the severity of the sclerosis are usually improved, with the results being less obvious for sclerodactyly [17]. The beneficial effect is particularly observed in generalized morphea where it can lead to complete remission [17], although unresponsive forms were also described [2]. Skin status remains unaffected in 25% [17] to 50% [14] of patients with systemic scleroderma. No clinical or biological elements seems to be helpful in predicting which, among these patients, will be responders.

Joint involvement

After skin sclerosis, rheumatological symptoms are the most frequently improved in responders. In his initial study, Thivolet [2] observed improvement of arthralgia in 6/20 patients. Similar findings were reported by Euller-Zigler [15] (9/10 patients), Guillevin [5] (10/25 patients) and Marzano [17] (7/11 patients). In one study, passive joint mobility was found increased for at least one major joint in 12/12 patients while articular mobility of small joints was improved for only 1/12 patients [17]. However, in a long term follow-up study, Guillevin [14] reported rheumatic benefit in only 1/29 patients. Given the limited set of data available and the lack of standardized methodology which does not allow for combined-analysis, these encouraging data should be considered carefully.

Raynaud's phenomenon

In Thivolet's [2] initial report, out of 16 patients presenting Raynaud's phenomenon, 9 experienced less intense vascular effects following treatment. More recently, in Marzano's [17] study, 3/8 patients similarly improved. Despite these cases, Raynaud's phenomenon was almost never reported to be improved following FXIII infusions nor were digital cutaneous ulcerations.

Esophageal involvement

Dysphagia was reported to be improved in a limited number of patients [2, 3, 17]. A beneficial effect of FXIII on lower esophageal sphincter pressure was clearly demonstrated for two patients, although correlation with clinical improvement was not reported by the authors [16]. However, in several other studies, esophageal abnormalities were not altered in many patients, who were objectively evaluated and followed up. Therefore, the beneficial effect of FXIII on esophageal involvement remains at best controversial.

Lung disease

A very limited number of data seem to demonstrate a positive effect of FXIII on pulmonary disease. Indeed, favorable modifications of carbon monoxide transfer factor and forced vital capacity ranging from 5% improvement to a return to normal were observed [2, 15, 17]. However, some of these patients were receiving other drugs such as corticosteroids and D-penicillamine at the same time making FXIII efficiency assessment unreliable and, in many other cases, no benefit was observed. Therefore to date, FXIII action on pulmonary disease remains uncertain.

Other organs involved

When presents, Sjogren's syndrome, kidney, heart, skeletal muscle and non-esophageal gastrointestinal involvement were never reported to be improved following FXIII therapy. Similarly, hematologic abnormalities and autoantibodies remained unaffected.

CONCLUSION

FXIII is one of a very limited number of drugs which can clearly improve the quality of life in a large number of patients with systemic scleroderma. This beneficial effect is essentially related to the ability of this blood coagulation factor to improve skin sclerosis and to a lesser extent arthralgia and weakness. Furthermore, given the remarkable effects observed in generalized morphea, some authors have suggested that FXIII be the therapy of choice in severe forms of this disease [17]. Since to date no standard drug has been found to be of value in scleroderma in adequately controlled prospective trials, the combination of immunomodifiers, drugs that interfere with collagen production and symptom-specific treatments are used in an effort to modify the disease. Based on available data, FXIII should be considered as a valuable, symptom-specific treatment for skin sclerosis in scleroderma. Therefore the drug should be made available for prescription under strict clinical trial evaluation in countries where tight regulations have restricted its use. These multicentric trials should more precisely delineate FXIII use in skin sclerosis management. They should also address putative benefits of the drug on other organs such as the esophagus, lung, musculoskeletal apparatus. FXIII's alleged ability to prevent endothelial cell damage should similarly be investigated.

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