|Year : 2019 | Volume
| Issue : 1 | Page : 57-61
Interesting cases in autoimmune connective tissue diseases: Clinical pearls for diagnosis and management
Sajjan N Shenoy
Consultant Immunologist and Rheumatologist, Department of Clinical Immunology and Rheumatology, KMC Hospitals, Mangalore, Karnataka, India
|Date of Web Publication||14-Feb-2019|
Sajjan N Shenoy
KMC Hospital, Mangalore, Karnataka
Source of Support: None, Conflict of Interest: None
Rheumatological diseases are multisystem in nature and skin is often involved, and mirrors the internal involvement which affords us insight into the disease, both from a diagnostic point of view and also from a pathophysiological point of view. A few clinical cases which were initially perplexing, but subsequently diagnosed as mixed connective tissue disease, dermatomyositis, and polyarteritis nodosa, are being discussed here to highlight this point.
Keywords: Clinical diagnosis, dermatomyositis, mixed connective tissue disease, polyarteritis nodosa, rheumatological disease
|How to cite this article:|
Shenoy SN. Interesting cases in autoimmune connective tissue diseases: Clinical pearls for diagnosis and management. Clin Dermatol Rev 2019;3:57-61
|How to cite this URL:|
Shenoy SN. Interesting cases in autoimmune connective tissue diseases: Clinical pearls for diagnosis and management. Clin Dermatol Rev [serial online] 2019 [cited 2019 May 23];3:57-61. Available from: http://www.cdriadvlkn.org/text.asp?2019/3/1/57/252313
| Introduction|| |
The discipline of rheumatology is one of those subspecialties of medicine which relies heavily on accurate history and astute physical examination by the clinician. Due to the multisystem nature of the diseases encountered, a patient with a rheumatological disease often requires a multidisciplinary approach and cross-talk between the various specialty physicians that are involved in his/her care. The skin is frequently involved in autoimmune connective tissue diseases (CTDs). Hence, it is very important for the dermatologists to understand the systemic nature of the skin manifestations in patients with CTDs and vary their diagnostic and therapeutic approach appropriately. Further, the involvement of the skin affords us insight into the disease, both from a diagnostic point of view and also from a pathophysiological point of view. A few cases which serve to highlight this point are discussed below.
| Case Reports|| |
A 24-year-old female presented with a history of tightening and darkening of the skin involving the fingers and dorsum of hands, face, and feet, which has been slowly progressing over the past 2 years. There is no history of erythematous rash or photosensitivity. She also complained of pain involving knees and shoulders which was worse during periods of rest with significant early morning stiffness. She denies any other systemic symptoms. She has had no other known comorbidities. On examination, she has a limited cutaneous distribution of scleroderma with sparse salt and pepper appearance of the forehead and scalp region. She also has tender and swollen knees, suggestive of active synovitis [Figure 1] and [Figure 2]. A closer examination reveals digital pits, which are indicative of significant secondary Raynaud's phenomenon [Figure 3].
|Figure 1: (a) sclerodactyly with puffy fingers. (b) sclerodactyly with nail fold depigmentation|
Click here to view
|Figure 2: Effusion of the knees, left more than right, suggestive of active synovitis|
Click here to view
|Figure 3: (a) Multiple digital pits and stellate scars. (b) Single digital crusted ulcer|
Click here to view
Routine investigations revealed an essentially normal hemogram, except a raised erythrocyte sedimentation rate (ESR) at 65 mm/1st h. Liver function tests, renal function tests, urine routine examination, chest X-ray, and thyroid function test were all normal. Her rheumatoid factor was negative, but antinuclear antibody (ANA) by indirect immunofluorescence (IIF) was positive (3+) with a coarse speckled pattern at 1:80 dilution.
A diagnosis of limited cutaneous distribution systemic sclerosis seems obvious here based on the history and clinical examination findings of the skin and joints. However, a grave diagnostic error is in offing if a complete systemic examination is not carried out. Although the patient did not complain of any breathlessness, chest pain or leg swelling, a cardiovascular examination on auscultation revealed features of pulmonary arterial hypertension (PAH) – loud P2 at the pulmonary area with Grade 2 ejection systolic murmur. In addition, she had a raised serum creatine phosphokinase (CPK) at 1900 U/L, suggestive of subclinical myositis. Untreated, this may progress to more overt clinical myositis with the weakness of proximal muscles and subsequent disability related to the same. Further, a characterization of the antinuclear antibody by the extractable nuclear antigen (ENA) testing (often referred to as the “ANA Profile”) revealed strong positivity to anti-U1RNP antigen [Figure 4].
|Figure 4: Extractable nuclear antigen immunoblot showing various antigens that are being tested for|
Click here to view
With the additional clinical details and laboratory evaluation information, which could have been easily overlooked or not ordered in a busy dermatology outpatient clinic, the diagnosis now may be revised to mixed CTD (MCTD) with secondary PAH and subclinical myositis. Although they share some common features, MCTD and limited cutaneous systemic sclerosis are two separate clinicopathological entities with different prognostic implications, MCTD patients tend to have more “lupus-like” manifestations including myositis, hematological involvement, PAH, and occasionally renal involvement and are more responsive to immunomodulatory therapies. In contrast, systemic sclerosis is more of a vasculopathic disease, often resistant to standard immunomodulatory therapies.
Pearls for the dermatologist
- Always think beyond the skin. Consider spending some time examining the respiratory, cardiovascular, and other systems in a patient with suspected or obvious CTD
- There may be subclinical manifestations (such as myositis, PAH, and interstitial lung disease [ILD]) which need to be picked up on clinical examination or appropriate laboratory screening
- An ENA testing is worthwhile whenever it has a potential to alter the diagnosis, management, and prognosis– as in this case of MCTD versus systemic sclerosis.
A 53-year-old homemaker presented with symptoms of diffuse muscle aches for the past 2 months. She also has considerable muscle weakness and has difficulty in getting up from sitting position, climbing stairs and above shoulder activities. She also complains of a reddish rash involving the upper eyelids, elbows, knuckles, and fingers, which is nonpainful, nonitchy, and nonscaly. She denies any other systemic symptoms. She has no known comorbidities. On examination, she had classic dermatomyositis rash including heliotrope rash and Gottron's papules [Figure 5] and [Figure 6]. Proximal muscle power was reduced with power graded at Medical Research Council Grade 3 for the bilateral lower and upper limb. Rest of the systemic examination was normal.
On laboratory evaluation, she had a mild microcytic hypochromic anemia (Hb 9.8 g/dL), and rest of the hemogram was unremarkable. Liver function tests were normal except for raised transaminases (AST 240 U/L and ALT 283 U/L). Renal function tests, urine routine, chest X-ray were normal. ANA by IIF was positive (3+) with a coarse speckled pattern at 1:80 dilution. ENA Immunoblot was negative. Serum CPK was raised at 8900 U/L. A muscle biopsy done was consistent with inflammatory myositis – dermatomyositis.
A diagnosis of dermatomyositis was made, and the patient was initiated on oral prednisolone at a dose of 1 mg/kg/day along with azathioprine. Despite adequate drug therapy, she showed a declining trend in muscle power and by the 8th week, had Grade 1 power in the shoulder girdle musculature and also was unable to stand or walk without support. Skin rash showed features of progression with new onset shawl sign and vasculitic rash over the palms.
In this clinical situation, what could have the reason for the seemingly refractory nature of the inflammatory myositis? A repeat thorough clinical examination revealed the answer in the form of a palpable mass in the right iliac region which was nontender with the irregular surface. A USG evaluation of the abdomen and pelvis showed an ovarian mass with mixed echogenicity highly suggestive of an ovarian malignancy. Subsequently, a laparoscopic biopsy was performed which confirmed the diagnosis of adenocarcinoma of the ovary. Hence, a complete final diagnosis would be dermatomyositis with underlying adenocarcinoma of the ovary. The patient had considerable improvement in her muscle symptoms and rash after the commencement of chemotherapy for her ovarian malignancy.
Pearls for the dermatologist
- Whether myopathic or not, all patients with dermatomyositis/polymyositis should be evaluated for occult malignancies,
- Common malignancies include nasopharyngeal, ovarian, lung, and pancreatic carcinomas,
- Always get a chest X-ray, ENT evaluation, gynecological examination and an ultrasound examination of the abdomen and pelvis before the commencement of immunosuppressive therapies
- Maximum risk of developing/diagnosis of an underlying malignancy is in the 1st year after diagnosis. Repeated clinical examinations are necessary to pick up ones that occur later in the course of the disease
- Malignancy should be especially suspected in patients with more of necrotic lesions, striking poikiloderma and if inverse Gottron's papules (on the palms) are seen, it is a clue to ILD too.
A 36-year-old male presented with painful nodular lesions over both legs since 1 year. The nodules appear and then seem to resolve after a few weeks only to reappear again in few weeks. Over the past 2 months, some of the nodular lesions had also started to ulcerate. The patient denied any other systemic symptoms or any history suggestive of preceding infections. He had no known comorbidities and was a nonsmoker. On examination, he had tender nodular erythematous lesions over both legs, with ulcerative changes seen in a couple of nodules [Figure 7]. There was mild leg edema. Rest of the systemic examination was normal, including respiratory examination.
Laboratory investigations were unremarkable including hemogram, renal and liver function tests, chest X-ray, urine routine, and microscopy. Inflammatory markers (ESR and CRP) were normal. Serologies for HIV, hepatitis B and C were negative. The venereal disease research laboratory, ANA (by IIF), and antineutrophil cytoplasmic antibody (by IIF) were negative. Ultrasound abdomen and pelvis was unremarkable.
In view of unrevealing clinical examination and blood investigations, a superficial punch biopsy was performed which showed nonspecific mixed inflammatory infiltrates in the epidermis and the dermis. There were no definitive features of vasculitis, but perivascular infiltrates were seen. Direct immunofluorescence was negative for immunoglobulin or complement deposits.
In this situation, the diagnosis is elusive despite optimal investigations. What could have been done better to arrive at a diagnosis? The answer lies in having a “deep” incisional biopsy, which must include the full thickness of the skin as well as subcutaneous tissue. In this case, a repeat biopsy showed “fibrinoid necrotising panarteritis” of deep dermal vessels with intense perivascular neutrophilic infiltrates. Features of panniculitis surrounding the inflamed vessel were also seen. These findings are distinctive to the more common livedoid vasculopathy or erythema nodosum (EN). A diagnosis of cutaneous polyarteritis nodosa (PAN) was made, and the patient was started on oral steroids along with methotrexate to which he responded very well and had complete resolution of the symptoms and signs.
Pearls for the dermatologist
- Consider deep incisional biopsies including subcutaneous tissue whenever a “vasculitic” pathology is considered – because medium-sized vessels may be involved which are usually missed in a superficial biopsy. This also holds true in biopsy of nodular lesions. As another example, EN seen in Behcet's syndrome bears some important differences to that observed in sarcoidosis or inflammatory bowel disease in that many EN lesions of Behcet's syndrome have accompanying medium vessel vasculitis. Due to the vasculitic nature of the lesions, permanent pigmentation of the overlying skin can complicate the EN associated with Behcet's syndrome
- Cutaneous PAN is more common than previously thought. Most patients do not have systemic features and do not progress to the classic syndrome of PAN,
- They tend to have relapsing and remitting course. A steroid course followed by maintenance methotrexate or azathioprine may be warranted.
| Conclusion|| |
As exemplified by the cases just discussed, one needs to be alert to the possibility of co-existing systemic disease in a patient with cutaneous lesions. Accurate diagnosis and classification of the disease rely heavily on history and a thorough clinical examination. Appropriate investigations based on the clinical suspicion help in diagnosis and management. Even though rheumatologic diseases are associated with considerable disability, morbidity and mortality, early diagnosis and aggressive management of systemic disease offer a better prognosis and morbidity-free life for most patients. Hence, one should view the skin as a “window” to the underlying systemic disease and harness its informative power to our advantage.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed connective tissue disease – An apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med 1972;52:148-59.
Burdt MA, Hoffman RW, Deutscher SL, Wang GS, Johnson JC, Sharp GC, et al.
Long-term outcome in mixed connective tissue disease: Longitudinal clinical and serologic findings. Arthritis Rheum 1999;42:899-909.
Bennett R. Overlap syndromes. In: Firestein G, Budd RC, Gabriel SE, McInnes IB, O'Dell JR, editors. Kelley's Textbook of Rheumatology. 9th
ed. Philadelphia, PA: Elsevier Inc; 2013. p. 1431-51.
Gerami P, Schope JM, McDonald L, Walling HW, Sontheimer RD. A systematic review of adult-onset clinically amyopathic dermatomyositis (dermatomyositis siné myositis): A missing link within the spectrum of the idiopathic inflammatory myopathies. J Am Acad Dermatol 2006;54:597-613.
Klein RQ, Teal V, Taylor L, Troxel AB, Werth VP. Number, characteristics, and classification of patients with dermatomyositis seen by dermatology and rheumatology departments at a large tertiary medical center. J Am Acad Dermatol 2007;57:937-43.
Buchbinder R, Forbes A, Hall S, Dennett X, Giles G. Incidence of malignant disease in biopsy-proven inflammatory myopathy. A population-based cohort study. Ann Intern Med 2001;134:1087-95.
Hill CL, Zhang Y, Sigurgeirsson B, Pukkala E, Mellemkjaer L, Airio A, et al.
Frequency of specific cancer types in dermatomyositis and polymyositis: A population-based study. Lancet 2001;357:96-100.
Callen JP. Relation between dermatomyositis and polymyositis and cancer. Lancet 2001;357:85-6.
Pipitone N, Boiardi L, Olivieri I, Cantini F, Salvi F, Malatesta R, et al.
Clinical manifestations of Behçet's disease in 137 Italian patients: Results of a multicenter study. Clin Exp Rheumatol 2004;22:S46-51.
Morgan AJ, Schwartz RA. Cutaneous polyarteritis nodosa: A comprehensive review. Int J Dermatol 2010;49:750-6.
Ishiguro N, Kawashima M. Cutaneous polyarteritis nodosa: A report of 16 cases with clinical and histopathological analysis and a review of the published work. J Dermatol 2010;37:85-93.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]