Systemic sclerosis or scleroderma (SSc) is a rare and complicated autoimmune disease that presents with many challenging therapeutic quandaries. In this chapter, we will discuss and examine these frequently encountered treatment dilemmas through three illustrative cases. In general, we recommend adhering to five general principles in the everyday care of a patient with SSc.
PRINCIPLES OF MANAGING SCLERODERMA
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Define clinical phenotype: The disease expression is very heterogeneous.
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Evaluate for specific organ involvement: The disease is deeper than the skin.
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Define the clinical stage of the disease: The biology of the disease is dynamic and uniquely complex.
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Customize and redesign therapy: Specific focused therapy can make an impact.
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Complex patients with undefined therapies should be referred to specialty centers for novel therapeutic approaches.
A 31-year-old chef with no significant past medical history was in good state of health until 4 months ago when she began to notice a cold, numb, and tingling sensation in her fingers after going into the freezer or working with frozen food. Her fingers would turn pale and occasionally blue upon exposure to cold temperatures. However, minutes after rewarming them under hot water, her fingers would return to their baseline color and temperature. Several months later, she developed severe pain in the right index finger and called urgently because of a persistently pale fingertip and local skin breakdown. Examination did not reveal evidence of sclerodactyly or fibrotic skin, but nailfold microscopy showed several capillary dilatations and telangietasias were noted on her fingertips, palms, and lips. All the fingers were cold to the touch, and the index finger was mottled with cyanosis surrounded by erythema. Pulses were strong but an Allen’s test demonstrated compromised ulnar artery flow.
Differential Diagnosis
Raynaud’s phenomenon (RP) is a vasospastic disorder that can be characterized clinically into primary and secondary forms ( Table 13-1 ). Primary RP is suggested by the presence of a symmetric presentation, lack of tissue necrosis or gangrene, normal nailfold capillary examination, and a negative serologic status. Our patient clearly presents with secondary RP with features of limited SSc and now severe critical digital ischemia requiring immediate attention. Patients with limited SSc, positive anticentromere antibody, and evidence of microvascular disease on examination are more likely to have associated macrovascular disease resulting in digital ulcers or amputation.
A 57-year-old woman with a 1-year history of RP treated with nifedipine and no other significant past medical history presents with a recent history of swollen hands and forearms. The skin is red, edematous, and pruritic and is rapidly progressing proximally over the past 2 months. On examination, she has sclerodactyly and erythematous swelling of her skin extending from her wrists to her elbows. Nailfold microscopy revealed several capillary dilatations and dropouts. Her antinuclear antibody status was positive with a titer of 1:320 in a nucleolar pattern.
| Systems | Association |
|---|---|
| Rheumatologic | Scleroderma, systemic lupus erythematosus, vasculitis, myositis, Sjögren’s syndrome, undifferentiated connective tissue disease |
| Hematologic/ oncologic | Paraneoplastic phenomenon, cryoglobulinemia, cryofibrinogenemia, paraproteinemia, cold agglutinin syndrome |
| Endocrine | Thyroid disorders |
| Vascular | Thoracic outlet syndrome |
| Neurologic | Carpal tunnel syndrome, migraine headache syndrome |
| Environmental | Vibration injury, frostbite, emotional stress |
| Drugs/Toxins | Sympathomimetic drugs, chemotherapeutic drugs, interferon, nicotine, cocaine, ergotamines, caffeine, polyvinyl chloride |
Differential Diagnosis
Scleroderma can present in limited or diffuse form. The limited form involves area of the skin distal to the elbows or knees (with or without facial involvement), whereas the diffuse form presents with skin involvement extending above the knees or elbows or onto the trunk. Scleroderma must be differentiated from a wide range of rheumatologic and nonrheumatologic diseases that can mimic it because the therapeutic strategy is vastly different in each case. The diseases that can be encountered in a patient initially thought to have SSc include scleredema adultorum, scleromyxedema, morphea, nephrogenic fibrosing dermopathy, eosinophilic fasciitis, myxedema secondary to hypothyroidism, systemic amyloidosis, graft-versus-host disease, and postradiation fibrosis. Careful history taking and physical examination alone often yield the correct diagnosis, whereas occasionally a skin or tissue biopsy and appropriate laboratory testing aid in confirming the diagnosis.
Seven years after our 31-year-old chef presented with limited SSc and RP ( Case 1 ), she developed the insidious onset of shortness of breath. In the past 12 months, she experienced a significant decline in exercise tolerance and increasing fatigue. At present, she is dyspneic with moderate activity (e.g., climbing stairs). She denies having orthopnea, paroxysmal nocturnal dyspnea, cough, fever, chills, or weight loss. Six weeks ago, she noticed new-onset edema in her lower extremities.
Differential Diagnosis
The differential diagnosis for dyspnea in SSc is relatively broad, but the primary attention should be placed on the cardiac and pulmonary systems. Many cardiac complications are reported in SSc, including systolic and nonsystolic heart failure, conduction abnormalities, pericardial disease, myocardial inflammation, fibrosis, and coronary artery disease. The pulmonary complications are more commonly recognized in SSc, and they include pulmonary malignancy, bronchiectasis, pleura-based disease, drug-induced pneumonitis, pulmonary infections, pulmonary arterial hypertension (PAH), and interstitial lung disease (ILD). In the following discussion, we focus our attention on PAH and ILD because they are the most frequent pulmonary complications of SSc.
RAYNAUD’S PHENOMENON
Pathogenesis
There are three major biologic processes that occur in cases of SSc and digital ischemia. First, vasospasm occurs due to dysfunction in the thermoregulatory vessels of the skin and perturbation of small to medium arteries and arterioles of the peripheral circulation. This process presents clinically as RP ( Fig. 13-1 ). Next, there is a nonvasculitic vasculopathy that is associated with endothelial dysfunction and a fibrotic thickening of the intimal layer of small arteries, which ultimately leads to narrowing of the vessel’s lumen. Finally, there is occlusion of the involved vessels (arteries, arterioles, and capillaries) either secondary to advancing vasculopathy or thrombosis. These three processes result in critical ischemia, loss of digital tissue, and fibrosis. Management of critical ischemia attempts to address these underlying mechanisms.
Therapy
The primary goal in the management of RP is the prevention of digital ischemia ( Fig. 13-2 ) through the use of nonpharmacologic and pharmacologic measures. In the setting of acute digital ischemia, as in our case, rapid intervention using both treatment modalities is required. Please refer to Table 13-2 for a summary of therapeutic options for RP.
| Class | Intervention |
|---|---|
| Nonpharmacologic |
|
| Pharmacologic |
|
| Surgical |
|
Nonpharmacologic Therapies
The primary and most important nonpharmacologic therapy for prevention is the avoidance of cold ambient temperatures, particularly transitioning from a warm or hot environment to a cold one. Additionally, strategies to keep the body and extremities warm (e.g., dressing warmly or wearing insulating gloves) should be employed. Patients who have an acute ischemic event are best treated by having them rest in a warm environment (home or hospital) while insulating them with additional warm blankets. Other potential therapies include minimizing emotional distress (reducing sympathetic tone) and eliminating any vasoconstricting agents (e.g., use of tobacco or sympathomimetic drugs). Although behavioral therapies (e.g., biofeedback, autogenic training, and classic conditioning) are reported to be helpful, their benefit is controversial and they play no role in the management of acute ischemia related to SSc. As for our patient ( Case 1 ), she was admitted to a local hospital to rest, to keep her extremities warm, and to start pharmacologic therapy.
Pharmacologic Therapies
Calcium channel blockers are considered the first-line agents in the treatment of RP. This class of medication works by inducing arterial vasodilatation through stimulation of the smooth muscle cells, but they also reduce oxidative stress and inhibit platelet activation. Most published studies evaluating the efficacy of calcium channel blockers in RP have employed dihydropyridines including nifedipine, amlodipine, nisoldipine, isradipine, and felodipine. Both short- and long-acting formulations of calcium channel blockers decrease the intensity and frequency of ischemic attacks. The current recommendation is to use an extended-release formulation of nifedipine (30–90 mg/day) or amlodipine (5–20 mg/day) for treatment of nonurgent RP. For urgent cases of RP, a short-acting formulation of the medication is preferred but the titration must be done in a carefully monitored setting in order to prevent worsening of digital ischemia due to “stealing” blood flow away from a structurally compromised digital vessel or an undue decrease in systemic blood pressure. In reference to our patient ( Case 1 ), given the lack of vasodilator therapy, she was initiated on nifedipine 30 mg three times per day with dose titration.
Other Vasodilators
Sildenafil, a phosphodiesterase-5 inhibitor that has been well studied in the treatment of PAH, is thought to be effective in the prevention of RP attacks. A recent 2007 study of quinapril suggests that angiotensin-converting enzyme inhibitors are not effective in treating SSc-related RP. However, one study found that the angiotensin receptor blocker losartan (50 mg daily) was comparable to nifedipine (40 mg daily), showing a similar reduction in the severity and frequency of RP attacks. Other agents that may be helpful include serotonin receptor uptake inhibitors, topical nitrate, other phosphodiesterase inhibitors (pentoxifylline, cilostazol ), intermittent intravenous prostaglandins (iloprost), and sympatholytic agents (prazosin, an α1-adrenergic receptor blocker).
Treating the Vasculopathy
The mechanism of SSc vascular disease is not completely understood, and therefore, intervention to prevent or reverse the vascular disease is not yet defined. Recent data suggest that the use of statins may be helpful by increasing the number of endothelial progenitor cells or by direct effects on vascular remodeling. The vasoactive drugs (angiotensin receptor inhibitors, prostaglandins, calcium channel blockers, phosphodiesterase inhibitors, nitrates) are thought to aid in vascular remodeling as well. A controlled study reports that bosentan (62.5 mg twice daily), an endothelin-1 receptor inhibitor, can be effective in preventing new digital ulcers and improve hand function. Antiplatelet agents (aspirin) may reduce thrombosis and further vascular injury. Chronic anticoagulation is not recommended unless there is a concomitant hypercoagulable disorder.
Surgical Interventions
Sympathectomy is a viable option for patients with RP who are unresponsive to medical therapy and should be used if a critical ischemic event is not quickly responding. Localized digital sympathectomy with lysis of fibrosis around the vessel is effective for acute ischemia and has mostly replaced central sympathectomy. Improvement of RP after digital sympathectomy can be transient or prolonged. Last, careful assessment for reversible macrovascular disease should be conducted in the setting of RP with the aid of Doppler imaging if clinically warranted. If macrovascular disease is present, patient should be referred to vascular surgery to discuss potential procedures that may help to alleviate the occlusive process.
Treatment of Critical Digital Ischemia
Our patient ( Case 1 ) has signs and symptoms of critical digital ischemia and immediate attention with medical intervention is most important to prevent ulceration or digital loss. In addition to initiating nonpharmacologic therapies, starting or maximizing a vasodilator such as a rapid-acting calcium channel blocker is strongly recommended. Antiplatelet therapy (daily aspirin) and unfractionated or low-molecular-weight heparin (1 mg/kg subcutaneously twice daily) should be initiated for 1 to 3 days if signs of larger vessel occlusion are present. Chemical sympathectomy performed by injection of lidocaine or bupivacine locally at the base of a digit rapidly reduces pain and reverses vasospasm. Local nitroglycerin gel applied to the affected areas may also be of some benefit. Although botulinum toxin injections are reported to improve digital ulcer healing and RP, the experience with this treatment is too limited and thus not recommended during an acute crisis. A prostaglandin or prostaglandin analog can be initiated if the above-mentioned measures are not helpful. Epoprostenol, iloprost, or prostacyclin analogs can be administered through a peripheral line continuously for 3 to 5 days in a closely monitored setting.
Cutaneous Manifestation in Scleroderma
It is fair to say that no agent has yet proven to be effective in controlling SSc. There are two major treatment strategies for cutaneous manifestation of SSc. The first strategy is to employ immunosuppressive therapy during the initial phase of active cutaneous inflammation ( Fig. 13-3 ) with tissue repair and before irreversible fibrosis occurs. The goal is to suppress the inflammatory cells that secrete proinflammatory cyokines (e.g., transforming growth factor-β) that activate and propagate the fibrotic pathway in skin and tissue. The second strategy is to employ an antifibrotic agent for the treatment of fibrotic skin ( Fig. 13-4 ); however the efficacy of these agents is questionable. Examples of such antifibrotic agents that have yielded disappointing results in clinical trials include D-pencillamine, interferons, and relaxin. New agents that are promising include anticytokines (e.g., anti–transforming growth factor-β1; anti-interleukin 13) and tyrosine kinase inhibitors (e.g., imitanib, dasatanib). So far, these agents are not yet fully studied, and thus, we will focus our discussion on the available immunosuppressive therapies used during the active inflammatory phase of the skin disease.
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