Find the groove and follow it to a rheumatology diagnosis
A 58 year-old Caucasian female was referred to rheumatology for further evaluation of bilateral lower extremity skin tightening. A massage therapist, who was providing treatment for the patient’s generalized musculoskeletal pain (which was initially believed to be the result of injuries sustained in a car accident), first noted the patient’s skin changes.
Another symptom that developed was right wrist pain, several weeks after the patient repaired a barbed wire fence. No other joint symptoms were present. A complete review of systems (ROS) was negative other than a sensation in her lower extremities described as “little sparks.” Raynaud’s phenomenon and fever were specifically absent. She was able to communicate her symptoms without shortness of breath or cough.
Labs ordered by the referring providers included a normal complete blood count, with the exception of an elevated absolute eosinophil count of 0.79 (normal: 0-0.4). Electrolytes, glucose, liver and kidney function tests, urinalysis, cholesterol profile, NT-Pro-beta-naturetic peptide (NT- Pro-BNP,) vitamin B12, folate and thyroid function tests were normal. Rheumatologic testing included a normal sedimentation rate, antinuclear antibody (ANA), and extractable nuclear antigen screen (ENA). A C-reactive protein (CRP) was elevated at 14.7 (normal: 3-8). An echocardiogram was unremarkable.
Rheumatology laboratory testing is completed in steps. The antinuclear antibody test (ANA), often used by primary care providers to screen for lupus, actually helps identify a variety of autoimmune disorders. If the ANA is positive, the next step by providers is to further investigate using an ENA screening test. In many labs, a positive ENA triggers the next tier of testing for antibodies of SSa, SSb, Scl-70, RNP, SM and Jo-1. These serologic tests help identify diagnoses such as systemic lupus erythematosus, Sjogren’s syndrome, systemic sclerosis/scleroderma, myositis and mixed connective tissue disease.
Along with normal vital signs, the patient’s heart, lung, abdominal and joint exams were normal. Notably, the skin of her fingers was unremarkable.
But the remaining skin examination demonstrated multiple abnormalities. Her anterior neck was almost tethered to her chest due to skin tightness. From wrist to mid-biceps bilaterally, her skin demonstrated a woody induration. An obvious long, linear groove was present on the interior aspect of her right arm. The upper medial arm skin showed cobblestoning, or a dimpled skin texture (similar to an orange rind).
Thickened skin in the interscapular region, lower lumbar region, anterior chest and anterior pelvic region was also present. Extensive tightness caused a prominent sheen on the skin of both lower extremities. From lateral thighs to dorsal midfoot, scattered areas of skin were warm, dusky and erythematous.
The predominance of diffuse skin tightening combined with peripheral eosinophilia narrowed the differential diagnosis to five major disorders: Churg-Strauss disease, eosinophilic fasciitis, lymphadenopathy, morphea profunda, and systemic sclerosis/scleroderma.
- Churg-Strauss syndrome (CSS), or eosinophilic granulomatosis with polyangiitis (EGPA), was a diagnosis briefly entertained due to the patient’s eosinophilia. However, no systemic organ damage was present as can be seen in CSS. With CSS, tissue damage to the heart, lungs and kidneys can be permanent. It occurs from vasculitis caused, in part, by high numbers of eosinophils in peripheral blood and tissue. Common skin changes of CSS are rash, purpura or petechiae.
- Eosinophilic Fasciitis (EF) causes an abrupt onset of pain and muscle weakness, along with erythema and swelling of the skin and subcutaneous tissue. It may be localized, such as in extremities; or it may be diffuse, including the trunk and abdomen. It may or may not be symmetrical. Physical exam of the skin often demonstrates a groove sign and peau d’orange (skin of the orange), meaning, a cobblestoned appearance that is like the skin of an orange. The diagnosis of EF depends on tissue biopsy, since no single laboratory test can identify the disease.
- Lymphadenopathy (generalized) can cause a skin sheen appearance from edema in the extremities due to an obstruction of lymph drainage. Lymphadenopathy can be caused by a variety of diseases as well as medications.1 HIV infection, Mycobacterial infections, mononucleosis, systemic lupus erythematosus (SLE) and serum sickness are a few of the diagnoses that can cause lymphadenopathy.1 Medications such as phenytoin, an anti-epileptic medication, can also cause lymphadenopathy.1 In this patient, no lymph nodes were palpable and sheen appearance was secondary to skin thickening.
- Morphea Profunda (MP), a primary dermatologic problem, can be part of the differential diagnosis ins ome rheumatologic diseases. The patient’s scattered areas of warm, dusky, erythematous skin raised this possibility. In MP, patchy sclerotic skin plaques change over time to firm sclerotic plaques, which can cause contractures and inability to perform activities of daily living. MP is associated with an elevated ANA,2 and like EF, must be confirmed by biopsy.
- Systemic sclerosis/scleroderma (SSc) presents with skin thickening, especially of the hands (sclerodactyly), and often with systemic manifestations as well. SSc patients commonly have Raynaud’s phenomenon (RP). RP is a distinctive blanching of white, red and blue/purple discoloration of the digits. These color changes reflect arterial vasospasm and cyanosis related to poor blood flow. It is very important to recognize that RP is present in 3% to 15% of the general population. For RP to be suggestive of scleroderma, it must be accompanied by nailfold capillary (cuticle) dilation and paired with positive scleroderma antibodies. Of the latter, 70% to 80% have a chance of presenting with scleroderma within 2-3 years.3 Sclerodactyly, the hallmark physical finding of SSc, was notably absent in this patient.
Rationale for Diagnostic Studies
The patient’s ROS and exam precluded any internal organ involvement by a systemic disease such as CSS. Workup and history eliminated lymphadenopathy by a negative medication review and absence of infection. A negative ANA and sclerodactyly ruled out SSc.
When evaluating most rheumatological conditions, it is prudent to request a rheumatoid factor (RF) test and an anti-cyclic citrullinated protein (anti-CCP) antibodies test. Since this patient’s physical exam did not demonstrate any objective indication of inflammation in the joints, these labs were not ordered.
Despite her lower extremity skin findings of thickening, duskiness and erythema that suggested a possible diagnosis of MP, the patient had a negative ANA. The patient’s physical finding of a long, linear groove in the upper arm, combined with peau d’orange skin changes and elevated peripheral eosinophil count, made the rare condition of EF surface as the most likely diagnosis. The patient was referred to our dermatology department for a deep-tissue skin biopsy, which confirmed the diagnosis.
Visual Diagnostic Evidence
This patient’s finding of the “groove sign” (Figure 1) is demonstrated by elevating the limb, causing the peripheral venous pressure to fall, and in turn causing the superficial layers of skin to bow inward.4 Cobblestoning, or peau d’orange, is another skin finding suggestive of EF (Figure 2). For this patient, biopsy pathology indicated “fibrosis and inflammation is centered mostly upon the fascia in a pattern suggestive of eosinophilic fasciitis” (Figures 3 and 4).
Prescriptions Can Trigger EF
The etiology of eosinophilic fasciitis is unknown. In 1975, Shulman first identified that excessive physical activity may be a common precipitating event,5 such as this patient’s repair of a barbed wire fence. Not only a patient’s physical activity, but provider actions such as prescription practices can also trigger the disease. These common prescription medications, simvastatin,6 atorvastatin,7 phenytoin,8 ramipril,9 and subcutaneous heparin,10 are also associated. In the 1980s and 90s, L-tryptophan, an over-the-counter sleep remedy, had been linked to a similar physical presentation caused by contaminated supplies of this product from Japan. Further investigations demonstrated the product can still cause this problem.11 In addition to medications, uncommon bacterial infections such as Borreliosis,12 and Mycoplasma arginini,13 have been also been associated with EF.
Controlling, Not Curing
Compared to other rheumatologic illnesses, EF does not have an identifying serologic test. In this patient, joint findings are absent, but skin findings of peau d’orange/cobblestoning and the groove sign suggest the diagnosis. Magnetic resonance imaging can be used to target the best deep tissue biopsy location.14 Biopsy is considered the “gold standard” for diagnosis.
As with many autoimmune illnesses, the treatment of EF is geared to the control of the disease rather than the cure. Corticosteroids and immunosuppressants are used in combination to decrease inflammation in a race similar to the tortoise and the hare. “Tortoise-like” immunosuppressants, such as hydroxychloroquine and methotrexate (MTX), may take several months to have a therapeutic impact. The “hare-like” action of prednisone quickly starts working.
In this case of eosinophilic fasciitis, prednisone was used in combination with MTX and hydroxychloroquine because the skin presentation was diffuse.15 Prednisone will be tapered and discontinued once acute phase reactants (in this patient, the CRP) are in normal limits. MTX and hydroxychloroquine will continue, and dosage adjustments should be made, to control the disease. This patient’s care has been returned to her referring providers.
Though eosinophilic fasciitis is considered a rare autoimmune disease, nurse practitioners, physician assistants and other front-line providers may often see patients with skin thickening. Finding a skin groove should immediately help connect the providers’ differential diagnosis with the possible presence of a rheumatologic condition.
- Fletcher RH. Evaluation of peripheral lymphadenopathy in adults. In: Boxer LA, ed. UpToDate. Waltham, Mass.: UpToDate; 2015. http://www.uptodate.com/contents/evaluation-of-peripheral-lymphadenopathy-in-adults
- Jacobe H. Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults. In: Callen J, ed. UpToDate. Waltham, Mass.: UpToDate; 2015. http://www.uptodate.com/contents/pathogenesis-clinical-manifestations-and-diagnosis-of-morphea-localized-scleroderma-in-adults
- Firestein GS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR. Kelley’s Textbook of Rheumatology (9th ed.) Philadelphia, PA: Elsevier Saunders; 2013.
- Pinal-Fernandez I, et al. Groove sign in eosinophilic fasciitis. Lancet. 2014;384:1774.
- Shulman LE. Diffuse fasciitis with eosinophilia: a new syndrome? Trans Associate Am Phys. 1975;88:70-86.
- Choquet-Kastylevsky G, Kanitakis J, Dumas V, Descotes J, Faure M, Claudy A. Eosinophilic fasciitis and simvastatin. Archives of Internal Medicine. 2001;161:1456-1457.
- Degiovanni C, Chard M, Woodlons A. Eosinophilic fasciitis secondary to the treatment of atorvastatin. Clinical and Experimental Dermatology. 2006;31:131-132.
- Buchanan RR, Gordon DA, Muckle TJ, McKenna F, Kraag, G. The eosinophilic fasciitis syndrome after phenytoin (dilantin) therapy. Journal of Rheumatology. 1980;7:733-736.
- Serratrice J, Pellissier JF, Champsaur P, Weiller PJ. Fasciitis with eosinophilia: a possible causal role of angiotensin converting enzyme inhibitor. Revista de Neuroliga. 2007;163: 241-3
- Cantini F, Salvaran C, Olivieris I, Padula A, Seneci C, Bellandi R. Possible association between eosinophilic fasciitis and subcutaneous heparin use. Journal of Rheumatology. 1998; 25: 383-385.
- Varga J. Risk factors for possible causes of systemic sclerosis (scleroderma). In: Axford JS, ed. UpToDate. Waltham, Mass.: UpToDate; 2015. www.uptodate.com. Accessed April 16, 2015.
- Granter SR, Barnhil RI, Dura P,. Borrelial fasciitis: diffuse fasciitis and peripheral eosinophilia associated with Borrelia infection. American Journal of Dermatology. 1996;8: 465-473.
- Sillo P, Pinter D, Ostorhazi E, Mazan M, Wikonkal N, Ponyai, K. Eosinophilic fasciitis associated with Mycoplasma arginini infection. Journal of Clinical Microbiology. 2012;50: 1113-1117.
- Moulton S, et al. Eosinophilic Fasciitis: spectrum of MRI findings. American Journal of Radiology. 2005;184:975-978.
- Lebeaux D, et al. Eosinophilic fasciitis (Shulman disease). Best Practice & Research Clinical Rheumatology. 2012;26:449-458.