A 39-year-old woman with Lupus, Myositis, and a Recalcitrant Vasculopathy

Authors


CASE PRESENTATION

Chief symptom

A 39-year-old Thai woman with a history of lupus was transferred for recalcitrant vasculopathy of her hands and suspicion of myositis.

History of the present illness

The patient had been given the diagnosis of systemic lupus erythematosus (SLE) 10 years before presentation when she developed a malar rash, Raynaud's phenomenon, arthralgias, alopecia, and sicca symptoms. She was treated with hydroxychloroquine alone until 6 months before presentation, when she developed digital ulcerations and leukopenia. Hydroxychloroquine was discontinued by her primary rheumatologist and prednisone 60 mg daily was initiated. Over the next 3 months, the patient was admitted to an outside hospital several times and treated with intravenous methylprednisolone for recurrent hand vasculopathy, digital ulcers, and progressive anemia.

Three months before presentation to our center, the patient developed intermittent fevers and severe proximal lower extremity myalgias associated with weakness. Her hand lesions were only partially responsive to intravenous glucocorticoids, and the lower extremity pain and weakness persisted despite this therapy. Extensive evaluation of her fevers, including routine blood, urine, and sputum cultures as well as viral and fungal serologies, determined no infectious etiology. Additional evaluation included computed tomography of the chest, which demonstrated scattered bilateral pulmonary nodules measuring up to 8 mm in size. Malaria smears were negative. A tuberculin skin test was negative, and a QuantiFERON assay (Cellestis Limited) was indeterminate. Acid-fast and fungal stains from induced sputum were negative.

The patient was treated empirically with broad-spectrum antibiotics, but her symptoms persisted. Thoracolumbar magnetic resonance imaging (MRI) was performed to evaluate her lower extremity pain and weakness. There was no evidence of transverse myelitis, paravertebral abscess, or malignancy. Muscle enzymes, including creatine kinase (CK), aldolase, aspartate and alanine aminotransferase, and lactate dehydrogenase (LDH) levels, were within normal limits. However, an MRI study of the thighs displayed scattered enhancement in the bilateral quadriceps. This was believed to be consistent with inflammatory myositis. The patient was transferred for further evaluation and management.

Upon transfer, the patient reported severe fatigue, diffuse myalgias that primarily affected the thighs, and pain and swelling in the joints of her hands and knees. She noted some healing of her hand ulcerations, but patchy cyanosis of her fingertips persisted. She denied any other skin lesions or photosensitivity. She reported weakness in both legs but felt that the strength in her upper extremities and neck was normal. She denied dysphagia, dysphonia, and dyspnea.

Past medical history

The patient is gravida 2, para 2. She had been diagnosed as having anemia in the past, but details of that evaluation are not clear. She also has a history of depression but had not received consistent therapy for that problem. She had a remote history of a positive tuberculin skin test.

Medications

The patient's medications included prednisone 30 mg daily, calcium, and vitamin D. Hydroxychloroquine had been discontinued approximately 3 months earlier. Over the previous month she had been admitted to an outside hospital, during which she had received prednisone at dosages ranging from 30–60 mg daily and had been treated with several antibiotics, including vancomycin, ciprofloxacin, and ceftriaxone.

Family and social history

She is a married mother of 2 children and lives in Northern California. She had moved to the US from Thailand 15 years before presentation and has not traveled to Thailand in the previous 2 years. She has no history of alcohol, tobacco, or other drug use.

Review of systems

The patient denied cough, shortness of breath, chest pain or pleurisy, dysuria, diarrhea, nausea, or vomiting. She also denied sicca symptoms, hematuria, and oral or genital ulcers. She had noted both diffuse and frontal hair thinning over the past 2 months.

Physical examination

The patient was an ill-appearing woman who looked her stated age. She was febrile, with an oral temperature of 38.5°C. Her heart rate was 110 beats/minute, her respiratory rate was 16/minute, and her oxygen saturation was 98% on room air. Aside from the patient's tachycardia, the cardiopulmonary examination was unremarkable. The skin examination revealed livedo reticularis over the palmar surfaces of both hands, with dry gangrene of multiple fingertips extending just proximal to the nailfolds. There was moderate synovitis of the proximal interphalangeal and metacarpophalangeal joints, as well as the left elbow and right knee. Both anterior thighs were tender to palpation but were not warm, erythematous, or swollen. There was mild, diffuse quadriceps atrophy bilaterally. Muscle strength was 4/5 in the quadriceps and hamstrings, but 5/5 in the deltoids, biceps, triceps, hip flexors, and hip extensors. There was no weakness of neck flexion, and the distal strength was intact in both the upper and lower extremities.

Laboratory investigations revealed a hematocrit of 25% (normal range 38–46%) with a mean corpuscular volume of 78 units (normal range 82–98). The erythrocyte sedimentation rate and C-reactive protein level were both elevated at 40 mm/hour (normal value <20) and 2.2 mg/dl (normal value <0.9), respectively. The antinuclear antibody (by HEp-2 immunofluorescence) and anti–double-stranded DNA antibody assays (by the Crithidia luciliae method) were positive at titers of 1:160 and 1:320, respectively, but antibodies to the Ro, La, Sm, and U1 RNP antigens were negative. Assays for anticardiolipin antibodies, the lupus anticoagulant, and anticentromere and anti–Jo-1 antibodies were negative. The serum C3 and C4 levels were both low, at 62 mg/dl (normal range 86–184) and 14.8 mg/dl (normal range 20–59), respectively. Repeat measurements of the serum CK, aldolase, aspartate and alanine aminotransferase, and LDH concentrations were all within the normal limits.

A repeat MRI of her thighs revealed extensive areas of T2 signal within the hamstrings, vastus lateralis, intermedius, and medialis muscles (Figure 1). These findings were similar, although slightly worsened, from prior outside MRI and were again interpreted as being consistent with inflammatory myositis. An electromyelogram (EMG) revealed increased spontaneous fibrillation potentials in both thighs consistent with inflammatory myositis.

Figure 1.

Magnetic resonance imaging (MRI) of the left thigh (axial) and bilateral thighs (coronal). A, axial, and B, coronal T2-weighted MRI with fat saturations taken 4 months after the onset of thigh pain shows progressive extensive edema consistent with inflammatory myositis. Although more prominent on the left, inflammation is noted bilaterally on coronal imaging (arrows delineate representative areas of edema/inflammation).

The patient was treated for a presumed SLE flare while additional evaluation proceeded. Her treatment regimen included hydroxychloroquine 400 mg daily, methotrexate 15 mg weekly, methylprednisolone 30 mg daily, and vasodilator therapy with sildenafil 25 mg twice daily. Vancomycin and voriconazole were also initiated empirically, the latter to treat a possible fungal infection manifested by the pulmonary nodules. The patient's arthritis, Raynaud's phenomenon, and digital ulcerations improved somewhat on this regimen. However, her generalized malaise, fevers, and lower extremity myalgias continued unabated. A diagnostic test was performed.

CASE SUMMARY

The patient is a 39-year-old Thai woman with a history of SLE who presented with several months of digital vasculopathy and ulcerations, fevers, weight loss, inflammatory arthritis, and a painful proximal myositis.

DIFFERENTIAL DIAGNOSIS

We will review the differential diagnosis, formulated according to the patient's constellation of symptoms, signs, and findings in the evaluation to date.

Digital vasculopathy and ulceration

Raynaud's phenomenon is a common manifestation of most autoimmune connective tissue diseases. However, the presence of digital ulcerative lesions implies an underlying vascular process beyond that seen with vasospasm alone. Vascular involvement is reported in 10–40% of SLE patients and can be grossly divided into thrombotic or inflammatory causes (1). The presence of antiphospholipid antibody syndrome is the most common cause of vascular thrombosis, although rarer cases such as thrombotic thrombocytopenic purpura have been reported in active SLE (1). Vasculitis in SLE can range from mild and asymptomatic to fulminant and organ threatening.

Among SLE patients with vasculitis, more than 90% have cutaneous disease (2). Deep biopsies in these patients are usually contraindicated because of concerns related to wound healing. The pathogenesis of these lesions is related to endothelial damage from various causes, including but not limited to immune complex deposition, complement activation, and the presence of anti–endothelial cell antibodies (3). The exclusion of a thrombotic tendency is essential in such cases, particularly by serologic testing for antiphospholipid antibodies (aPL). In addition, patients with overlap connective tissue disease syndromes sometimes experience digital ischemia caused by vasculopathies that resemble systemic sclerosis more than true vasculitis. In such settings, attempts at vasodilation form the central approach to therapy. The absence of aPL, the lack of features to suggest a scleroderma-like condition, and the improvement of our patient's digital ischemia while receiving glucocorticoids all suggested an inflammatory basis of her digital ischemia.

Fever

Our patient's intermittent fevers to greater than 38.3°C for more than 3 weeks meet the classic definition of fever of unknown origin (FUO) (4). Reviews of large case series of FUO suggest that a primary inflammatory process is responsible for the fever in 22% of cases (5). Infection and malignancy account for 16% and 7%, respectively, and miscellaneous conditions account for an additional 16%. More than half of cases of FUO have remained without diagnoses in some series. Given that our patient has a well-established diagnosis of SLE, it is tempting to attribute her entire presentation, including the fevers, to active lupus. However, the failure of her fevers to respond to moderately high doses of glucocorticoids should certainly make one consider other entities, particularly infection. Because our patient was born in Thailand and has traveled to areas where tuberculosis and malaria are endemic, the index of suspicion for these diseases and other infections is heightened. Moreover, her treatment with high-dose glucocorticoids increases her risk for an infectious cause of her fevers.

Myopathy and myositis

Myopathy and myositis can be caused by a range of pathologies, including endocrine, metabolic, toxic, primary inflammatory, cancer-associated, sarcoidosis, or infectious etiologies. Normal levels of electrolytes and thyroid function tests make endocrine causes unlikely. The acute onset of myopathy in middle age and the lack of significant elevations in muscle enzymes argue against genetic and metabolic myopathies.

Although many drugs have been associated with toxic myopathies, the most commonly implicated ones are lipid-lowering agents and glucocorticoids. This patient had not been exposed to lipid-lowering agents, but steroid myopathy can occur within weeks to months of steroid use, and our patient had received high-dose glucocorticoids for the past several months. Steroid-induced myopathy can occur acutely after very high-dose, usually parenteral, glucocorticoid administration, but it more commonly manifests as an insidious onset of bilateral, painless, proximal muscle weakness, often affecting the lower extremities before the upper extremities. Although the timing and location of this patient's weakness are consistent with steroid-induced myopathy, this process typically shows no signs of inflammation on MRI, and her painful myalgias are not characteristic of a steroid myopathy.

Primary inflammatory myositis usually has an autoimmune origin and can be associated with dermatomyositis, polymyositis, or other connective tissue diseases, including SLE. Although myalgia can be seen in 40–80% of patients, the incidence of frank inflammatory myositis has been reported in only 5–11% of patients with SLE (6). Inflammatory myositis is characterized by bilateral proximal muscle weakness and is usually, although not universally, accompanied by elevated muscle enzymes. Although myalgias are common, tenderness to palpation is infrequent. The proximal bilateral nature of this patient's symptoms and inflammation noted on MRI are consistent with a primary inflammatory myositis, especially in the setting of active SLE. However, the presence of pain out of proportion to weakness, normal levels of muscle enzymes, and failure to respond to high-dose immunosuppression make consideration of alternative processes necessary.

An additional diagnostic consideration includes sarcoid myopathy. Up to 70–85% of individuals with sarcoidosis demonstrate granulomas by muscle pathology; however, only 0.5–2.5% of patients are typically symptomatic (7). The most common presentation of sarcoid myopathy is the insidious onset of a proximal myopathy characterized by weakness, myalgia, and myopathic findings on EMG (8), which may or may not be associated with elevations in muscle enzymes. Less common forms of sarcoid myopathy include an acute myositis with rhabdomyolysis and an asymptomatic nodular form (8). MRI findings of T2 enhancement can be helpful in the identification of sarcoid myopathy (7), although, in the absence of clinical sarcoidosis elsewhere, only biopsy can differentiate this entity from polymyositis. Even though sarcoid myopathy is usually responsive to steroids, recent case series suggest that relapse is common (6).

Infectious myositis can be caused by viral, bacterial, parasitic, or fungal infections. Acute and subacute viral myositis usually present with mild, self-limited myalgias in association with systemic viral infections (such as influenza); alternatively, viral myositis can present with severe rhabdomyolysis and profound elevation of muscle enzymes. Our patient's presentation was not consistent with either of these circumstances. Human immunodeficiency virus (HIV), however, has been reported to cause a chronic proximal myopathy that can be associated with nonspecific myalgias, elevated muscle enzymes, and abnormal electromyography closely mimicking polymyositis. However, our patient had a negative test for HIV.

Parasitic myositis is uncommon in the US and is typically acquired abroad. The presence of eosinophilia and a consistent travel history may suggest a parasitic etiology for myositis; however, most are self-limited and peak within 5–6 weeks after infection, followed by resolution after the larvae become encapsulated and calcified within the muscles (9). Although the use of glucocorticoids may have blunted an eosinophilic response, the lack of recent travel and the persistence of symptoms argue against parasitic myositis. Fungal myositis is rare and limited to case reports. However, given immunosuppression with glucocorticoids in the setting of fever, rash, and muscle tenderness, fungal causes such as the Candida species (10) and locally endemic mycoses such as coccidioidomycosis should be considered.

Pyomyositis is a purulent infection of skeletal muscle that arises from hematogenous spread, usually with abscess formation (11). Pyomyositis generally presents with fever, pain, and cramping localized to a single muscle group, although multifocal involvement has been described, especially with delay in diagnosis or in the setting of an immunocompromised host (8). Pyomyositis is typically caused by hematogenous seeding of a damaged muscle by Staphylococcus aureus, including methicillin-resistant S aureus, with the second most common organism being group A streptococcus. Previously called “tropic pyomyositis” due to the relatively high prevalence in tropical Africa, the incidence is increasing in North America, especially among those with HIV and other causes of immunosuppression (9). Additionally, mycobacterial species can cause myositis by either direct extension from a contiguous source (e.g., an infected joint, bone, or abscess) or less commonly via bacteremic spread (12).

DIAGNOSTIC PROCEDURE

The many atypical features of this patient's myositis, including pain greater than weakness and lack of response to appropriate levels of immunosuppression typically used to treat connective tissue disease–associated myositis, led us to perform an open biopsy of the left quadriceps muscle. The muscle appeared grossly normal and microscopic examination demonstrated that the majority of muscle fibers maintained normal polygonal shape and size. However, 2 distinct foci of noncaseating granulomatous inflammation were identified, and both Fite and acid-fast bacilli preparations demonstrated mycobacterial organisms (Figure 2). Cultures from the muscle biopsy grew pan-sensitive Mycobacterium tuberculosis.

Figure 2.

Pathologic examination of thigh muscle biopsy. A, Hematoxylin and eosin stain (magnification × 10) revealing noncaseating granulomatous inflammation throughout muscle fascicles (arrow delineates granuloma.) B, Fite stain (magnification × 40) revealing the presence of acid-fast bacilli (arrow) within the area of granulomatous inflammation.

DISCUSSION

The connection between autoimmune disease and infection is often complicated by both the ability of infection to mimic the protean clinical manifestations of autoimmunity as well as the ability for infection to exacerbate underlying autoimmune activity. Tuberculosis is well recognized for its ability to affect essentially any body system, and therefore should be considered a diagnostic possibility even when clinical signs and symptoms are atypical for mycobacterial disease (13). Herein we present a case of SLE complicated by tuberculous myositis that closely mimicked an immune myositis. The disease course and response to treatment emphasize the interaction between infection and autoimmune disease and the importance of maintaining a high clinical suspicion for infection in the setting of immunosuppression, particularly when there is a lack of expected response to such therapies.

Managing immunosuppressive therapy in patients with active autoimmune disease and concomitant infection presents a challenging dilemma to the clinician. Our priorities in managing this patient's care included controlling underlying rheumatic disease with immunosuppression while simultaneously performing a thorough infectious disease evaluation, which ultimately revealed tuberculous myositis.

During the prior several months, management had included intravenous and oral glucocorticoid regimens, which failed to control several of her disease manifestations, specifically, fevers, myalgias, and weakness. Although it appeared reasonable to assume that this patient's persistent muscle pain and inflammation were related to active SLE-associated myositis, her atypical presentation with muscle tenderness and fevers, as well as the lack of response to high-dose immunosuppression, indicated that infection was likely complicating her course. We speculate that much of her presentation could be due to systemic inflammation related to infection, thus fueling her SLE. Supporting this hypothesis is a recent case series identifying antecedent M tuberculosis infection as a significant risk factor for the development of active SLE (14). The inability to control her systemic inflammatory process with high-dose glucocorticoids was likely related to immune activation by her chronic infectious process and similarly, the contribution of glucocorticoids to enhancement of high mycobacterial load (12).

Extrapulmonary M tuberculosis is an increasingly common presentation of mycobacterial infection and rates are higher in the immunocompromised population, including those with HIV (13) as well as those intentionally immunosuppressed in the setting of organ transplant (15) or autoimmune disease (16). There have been numerous case reports documenting the occurrence of extrapulmonary tuberculous (17–19) and nontuberculous (20–24) mycobacterial infections in those undergoing immunosuppression for rheumatic diseases.

Retrospective case series have suggested that the incidence of both extrapulmonary M tuberculosis, as well as M tuberculosis in general, is increased in patients with SLE (15, 16). These studies also noted a significant delay in establishing the diagnosis, especially with the extrapulmonary form, due to a tendency to attribute systemic and nonpulmonary symptoms to the lupus process.

Tuberculous myositis is an uncommon manifestation of extrapulmonary M tuberculosis, and much of our current understanding is based on small case series (17, 18, 25). The largest series from Taiwan describes 35 patients with tuberculous myositis (26). Eighty-two percent of these patients required surgical debridement and the overall mortality rate was 14%. Also noted was a significantly poorer prognosis in patients who had received glucocorticoids prior to the onset of their myositis symptoms.

Few recommendations regarding the treatment of tuberculous myositis have been published. Case reports and case series report success with standard antituberculous drug therapy with the addition of surgical debridement when an abscess is present.

In conclusion, we present, to our knowledge, the first case of bilateral tuberculous myositis in a patient with active SLE. Our case is the first description of tuberculous myositis so closely mimicking a classic clinical presentation of autoimmune myositis. Given the patient's concurrent lupus activity with vasculopathy and synovitis and EMG and MRI results suggestive of inflammatory myopathy, the ultimate diagnosis was delayed. However, the atypical presentation with lack of elevation in muscle enzymes, preserved upper extremity and neck strength, muscle tenderness on examination, and persistent fevers all suggested an alternative etiology. Our case demonstrates the ability of infection to closely mimic manifestations of systemic autoimmune disease and the importance of carefully reconsidering a diagnosis when clinical response to immunosuppressive therapy is not as expected. In addition, infection often induces flares of disease in SLE patients, and immunosuppression is frequently necessary to control the underlying autoimmune disease while an infectious evaluation is pursued. Finally, this case demonstrates the value of muscle biopsy to confirm the etiology and diagnosis of inflammatory myositis, particularly in the setting of atypical features or unresponsiveness to immunosuppression.

FINAL DIAGNOSIS

Tuberculous pyomyositis associated with SLE flare.

FOLLOWUP

Treatment was initiated with ethambutol, pyrazinamide, isoniazid, and levofloxacin (with levofloxacin soon changed to rifampin after the discontinuation of voriconazole therapy). Within several days of initiation of antituberculous therapy, constitutional symptoms and proximal muscle pain and weakness began to improve. Additionally, there was significant improvement in hand vasculopathy and synovitis, thus allowing a rapid taper of her prednisone to 10 mg daily. Blood and sputum cultures were each subsequently confirmed to be positive for M tuberculosis by polymerase chain reaction amplification. Our patient was discharged home 4 days after the initiation of treatment, with near normalization of her strength within several weeks afterward. After being discharged from the hospital, our patient remained on relatively low levels of immunosuppression (methotrexate 15 mg weekly, hydroxychloroquine 200 mg daily, prednisone 5 mg daily). Over the subsequent 4 months, all clinical symptoms of lupus have remained stable with no further occurrences of digital ulceration, hand vasculopathy, or synovitis, suggesting improvement of lupus disease activity with treatment of the infection.

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