Chronic rejection remains a potential future consequence in hand CTA. Rejection amongst individuals having received a hand CTA are graded based on morphological features. There is agreement that progressive perivascular lymphocytic infiltrate occurs with increasing rejection with inflammation of the dermal stroma, epidermis and adnexa with epidermal apoptosis in severe cases. Scleroderma has been proposed as a clinical correlate for chronic rejection in facial allotransplantation based on potential parallels of pathophysiology and disease course (Sivakumar et al. 2010). Chronic changes in a nonhuman primate model of hand transplantation was characterized by arteritis, vasculopathy and intimal hyperplasia progressing to vessel occlusion. The grafts appeared pale and oedematous, these findings mirroring to a degree findings in progressive scleroderma (Mundinger et al. 2013). Previous studies have shown that skin deformity is a core stressor within the scleroderma population (Benrud-Larson et al. 2002).
Assessment of standardised photographs revealed a broad range of disease, from mild through to severe. The cohort was representative of the spectrum of changes that would be seen in a chronic rejection process. Presentations in 4 chronic hand rejection transplant recipients have involved a desquamative red papular rash, lichenification of the palm and dystrophic changes to the nail with eventual loss of the nail, similar charateristics seen in our scleroderma population (Ravindra et al. 2012).
In our study, with time appearance did not worsen. Furthermore, despite many subjects reporting skin changes as a major concern, no relationship could be seen between psychological wellbeing and severity of disfigurement. This implies that appearance alone is not a defining factor in patients’ perception of the severity of hand disease. However, this may in some way be related to the cross-sectional nature of our study. A longitudinal analysis of a larger cohort of patients would be useful (van Lankveld et al. 2007).
Individuals with scleroderma commonly suffer from rheumatic problems. Articular manifestations may be the presenting feature in the majority of patients, and clinically manifest as arthralgia, flexion contractures and in fewer cases as arthritis which have an impact on functionality (Pope 2003). In line with our cosmesis findings, disease duration appeared to have no effect on hand joint mobility. However, with increasing disfigurement, we saw worsening joint motion. Additionally, we identified that with longer disease duration, the more limited individuals were in their ADL. However, despite deterioration in mobility, patients were able to adapt remarkably well in managing their activities of daily living. Similar results have been found in other studies with chronic hand pathologies (Van Zelst et al. 2006). This most likely reflects the chronic deterioration in hand mobility, which enables adaptation. This may explain why psychological scores were not affected by decreasing range of motion. As we would expect, increases in ADL brought about a greater physical feeling of QOL.
The DASH was primarily used in the study to identify whether its use had similar outcomes to the International Registry on hand transplantation ADL questionnaire. The registry outcomes have never been applied to the scleroderma population before, and in demonstrating the correlation with SF-36 and the DASH, similarities between the two populations have been demonstrated which support the proposal that scleroderma is a useful clinical model for hand CTA rejection. People with higher scores on the DASH representing greater upper limb disability, were found to demonstrate poorer QOL outcomes with lower scores on both the physical and mental components of the SF-36.
Scleroderma affects hand function and appearance, which can lead to psychological distress. Psychological problems are common amongst patients with chronic illnesses such as scleroderma and may interact and exacerbate functional disability and global disease. 40% of individuals were borderline or classified as clinical cases with anxiety. Furthermore, 32% of the cohort either had borderline depression or were clinical cases. Despite the majority of participants falling within the non-case category, significant psychological distress was evident in a small proportion of the cohort. In our cohort, pain was a powerful predictor of depression and increasing feelings of subjective limb disability, therefore we would suggest that adequate pain control in these individuals requires careful consideration (Benrud-Larson et al. 2002).
It is striking that individuals with scleroderma appear to adapt their behaviour to cope with functional changes, such that levels of disability remain remarkably low. Many of the problems the condition poses are manageable, and psychological resilience appears high overall with a minority of patients exhibiting psychological distress that require clinical intervention. Nonetheless, ongoing and regular screening for both pain and psychological distress would be pertinent if chronic graft rejection were to take place, allowing for considerable scope for positive early intervention. Experience from solid organs transplantation shows that high numbers of acute rejection results in a higher incidence of chronic rejection. Similarly, in a rat hind limb model, nerve regeneration and muscle activity were shown not to be affected by a small number of acute rejections. However, with increasing acute rejection, there is a significant decline in function leading to atrophic and fibrotic muscle. There was evidence of mononuclear cellular infiltration (Unadkat et al. 2013). It has been suggested that the low rate of rejection observed in current hand allograft is attributed to the short follow-up and early recognition allowing reversal of acute rejection. Additional evaluation of acute and chronic rejection in human hand and face allograft is required to define its characteristics since no definite signs of chronic rejection are present in any allografts to date, including the longest surviving allograft of 12 years (Whitaker et al. 2008).
It may be that the connection between scleroderma and chronic rejection is not as strong as proposed within the model. The pathophysiological processes do somewhat differ, in that scleroderma manifests with thickening of connective tissue within the deep dermis, subcutaneous fat and muscular fascia, with thinning of tissues in chronic rejection. An important difference between those from the scleroderma and hand transplant cohort resides in the notion that hand amputees are healthy and selected for transplantation on the basis they do not have significant comorbidities impacting on infection and malignancy. In addition, transplantation of the hand is not life-saving and does not maintain long-term survival.