Introduction
Scleroderma is a rare disorder of the connective tissues with an enigmatic and complicated pathophysiology. Based on clinical and serological criteria, scleroderma can be defined as localized or diffuse systemic sclerosis. Patches of thickened skin are a symptom of localized scleroderma, which affects the skin and subcutaneous tissue. On the other hand, systemic sclerosis (SSc) is connected to several systemic symptoms, internal organ involvement, and a higher mortality rate. Although the precise cause of SSc is not fully understood, it is believed that genetic and environmental factors have a role in the onset of the disease. Vascular injury, autoimmunity, and tissue fibrosis are the defining features of systemic sclerosis. The clinical assessment, identification of the affected organs, and disease progression are essential for effective treatment. A crucial component of attaining better treatment results is early diagnosis.
The most widely used immunosuppressive drugs include cyclophosphamide, mycophenolate mofetil, methotrexate, azathioprine, and hydroxychloroquine. Any conclusive therapy cannot change the course of the disease or broadly acknowledged disease-modifying substance. The affected systems have, however, been successfully managed.
What Is Refractory Systemic Sclerosis?
Patients with systemic sclerosis face significant morbidity, which leaves them severely disabled. There is no treatment for this condition; only symptomatic relief is administered. A definition of "refractory" is an illness that defies a specific course of therapy. Refractory systemic sclerosis is a non-response to standard therapy at a certain time.
The hallmarks of systemic sclerosis with refractory manifestations include disease progression or insufficient response, regardless of the organs or systems involved, intolerance to therapy despite clinical response when the disease manifestation lacks an effective medical therapy, and after the exclusion of occult conditions or comorbidities that may mimic disease progression or non-response to therapy.
What Are the Clinical Manifestations of and Treatments for Refractory Systemic Sclerosis?
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Refractory Skin Involvement
The skin involvement in localized SSc is not the most problematic aspect, and in most instances, it is mostly treated locally with paraffin baths. In diffuse SSc, the skin condition typically improves over three to five years. Since skin involvement typically improves over time after peaking at around 18 months, it is difficult to classify it as refractory. However, calcinosis (deposition of calcium salts in the skin) is regarded as refractory as there is no effective treatment. Rituximab was also helpful in minor clinical trials, in vitro research, and case reports. Imatinib has demonstrated advantages in lowering skin fibrosis as an antifibrotic medication. However, more research is needed.
2. Refractory Vascular Involvement
Telangiectasia is common, particularly in localized SSc, and is deemed refractory when no cure exists. In addition, concurrent disorders such as proximal artery disease, vasculitis, thrombotic disease, or calcinosis that hinder ulcer healing should be eliminated before classifying the Raynaud phenomenon or digital ulcers as refractory to normal therapy. Surgery is occasionally the best option in refractory conditions, especially if there is diseased and necrotic tissue or if calcinosis is impeding ulcer healing. Rarely is a cervical sympathectomy advised. For elective instances, digital sympathectomy is proven to be helpful, but it is a very specialized treatment that is only carried out in a minimal number of centers.
3. Refractory Heart Involvement
Since SSc frequently runs asymptomatically and its symptoms may be connected to other non-cardiac aspects, heart involvement is common but sometimes missed. The EKG (electrocardiogram) alterations progress in severity score despite adequate treatment, the left ventricular dysfunction progresses despite heart failure optimized treatment or intolerance, or the heart failure symptoms and signs persist or worsen despite heart failure optimized treatment or intolerance are the distinguishing characteristics of refractory heart involvement in systemic sclerosis. To test for and prevent sudden death episodes, the patient should have echocardiography and 24-hour Holter EKG monitoring if they are asymptomatic. With a thallium scintigram, the silent ischemia disease can be accurately screened. There are no specific treatment suggestions for cardiac involvement in systemic sclerosis. Still, vasodilators such as calcium channel blockers and angiotensin-converting enzyme inhibitors have improved perfusion and function abnormalities.
4. Refractory Lung Involvement
Treatment-resistant lung involvement in systemic sclerosis is indicated by dyspnea that worsens over time with little exertion. Intravenous prostacyclin analogs must be administered continuously via intravenous infusion, there are many potential side effects (most notably pulmonary edema in patients with left heart disease or veno-occlusive disease), they are expensive, and they are only used in severe (WHO class IV and may be considered in class III) or refractory cases. Another alternative in WHO class III is inhaled iloprost, which has been shown to improve symptoms and boost exercise capacity. Imatinib reportedly treats refractory cases when combined with phosphodiesterase type-5 inhibitors and endothelin antagonists.
5. Refractory Kidney Involvement
Systemic sclerosis frequently has minor renal SSc involvement, which presents as proteinuria, hypertension, and mild renal impairment. Scleroderma renal crisis (SRC), which is more serious, is characterized by the sudden onset of accelerated arterial hypertension and/or fast-progressing oliguric renal failure while suffering from systemic sclerosis. Once ACE inhibitors are at the total dose, angiotensin II receptor blockers and calcium channel blockers can be added safely if necessary. However, they might not be enough to control the condition independently. Other antihypertensive traditional medications such as Clonidine, alpha-blockers, and Minoxidil are also beneficial for refractory hypertension, but beta-blockers should be avoided.
6. Refractory Musculoskeletal Involvement
Musculoskeletal system involvement is common in SSc, particularly early arthralgia and tendon sheath involvement in diffuse SSc. Musculoskeletal dysfunction causes contractures, abnormalities in the hand, and skin involvement. Refractory musculoskeletal signs include worsening or non-responsive arthritis despite typical DMARD therapy, no change in finger-thenar distance or an increase, the same number of friction rub tendons or worsening, and chronic myositis despite therapy. If myositis is refractory, with or without overlap, alternative treatments such as Cyclophosphamide and Rituximab may be considered. If arthritis is the primary characteristic and is unresponsive to traditional DMARD, treatment options include anti-TNF, Rituximab, Abatacept, or Tocilizumab. Steroids, like in other rheumatologic diseases, may help with some diffuse SSc features (lung, joints, and myositis), but Prednisolone dosage above 10 mg/day is linked to an increased risk of scleroderma renal crisis, so patients taking steroids need to be closely watched for blood pressure and renal function.
Conclusion
Systemic sclerosis is a serious condition in and of itself. Still, recent broad advancements in SSc physiopathology are opening up new views and prospects in SSc future treatments, especially for refractory cases. Drugs have demonstrated efficacy in small trials, but more extensive studies are either lacking or the outcomes still need to be discovered, which are much awaited.
