Interleukin-6 (IL-6) is implicated in the pathogenesis of both systemic juvenile idiopathic arthritis (SJIA) and syndrome of inappropriate secretion of antidiuretic hormone (SIADH), but the 2 have not been previously described as occurring together. We report a case of a 6-year-old girl with symptoms of arthralgia, daily fevers, evanescent rash, lymphadenopathy, and laboratory evaluation showing elevated inflammatory markers, consistent with SJIA. At presentation, the patient had hyponatremia with a sodium level of 128 mEq/L. She had low serum osmolality with elevated urine osmolality, consistent with SIADH. Hyponatremia improved temporarily during times of fluid restriction as expected in SIADH, but did not resolve until SJIA was treated successfully with tocilizumab, an IL-6 receptor antibody that inhibits IL-6 activity. The positive response to treatment with tocilizumab supports the role of IL-6 in the pathogenesis of both SJIA and SIADH. Patients with SJIA should be monitored for SIADH to avoid complications of untreated hyponatremia.

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is characterized by hyponatremia, low serum osmolality, elevated urine osmolality, and clinical euvolemia in the absence of diuretic medications.1 SIADH can be caused by malignancy, pulmonary diseases, neurologic diseases, medications, and inflammatory diseases, such as Kawasaki disease.1,2 The pathogenesis of SIADH in inflammatory diseases is thought to be associated with the cytokine interleukin-6 (IL-6).3,4 We report a case of a 6-year-old girl with hyponatremia due to SIADH at initial presentation of systemic juvenile idiopathic arthritis (SJIA), with improvement of hyponatremia after treatment with the IL-6 inhibitor tocilizumab.

A 6-year-old girl was admitted after having fever to a maximum temperature 102°F daily for 6 consecutive days. She also had symptoms of sore throat, cough, congestion, bilateral hip pain, and myalgias. On the day of admission, she developed a rash on her face and chest, as well as abdominal pain and vomiting. She denied joint swelling, conjunctival injection, and swelling or erythema of hands and feet. The patient was previously healthy. Immunizations were up to date. Family history was significant for ulcerative colitis in her father.

Physical examination at the time of admission showed a maculopapular, evanescent, erythematous rash on the trunk and perioral area that was most prominent during febrile episodes. There was bilateral cervical lymphadenopathy, including a 1-cm lymph node. She had pain and tenderness in her hips bilaterally, without swelling or erythema, and with full range of motion. The remainder of the examination was unremarkable with no tenderness, pain, or decrease in range of motion in other joints, no hepatosplenomegaly, and no cardiac murmur, rub, or gallop. There was no evidence of edema of the hands or feet, desquamation of the skin, conjunctival injection, or mucosal changes. Laboratory evaluation was significant for a sodium (Na) level of 128 mEq/L (normal range: 135–143 mEq/L), a white blood cell count of 38 900 L−1 (range: 4 400–11 000 L−1) with 91% neutrophils, a hemoglobin level of 10.5 g/dL (range: 10.6–14.6 g/dL), a platelet count of 516 000 L−1 (range: 150 000–400 000 L−1), a C-reactive protein (CRP) level of 225.17 mg/L (range: 0–10 mg/L), an erythrocyte sedimentation rate 130 mm per hour (range: 0–20 mm per hour), and a ferritin level of 1596 ng/mL (range: 10–120 ng/mL). Liver function tests, triglycerides, lactate dehydrogenase, uric acid, cortisol, and urinalysis were normal, including a normal aspartate aminotransferase (AST) of 26 IU/L and triglycerides of 124 mg/dL. Anti-nuclear antibodies were nonreactive. Evaluation for infectious diseases was negative, including multiple viral and bacterial culture and antibody tests. Imaging showed a normal chest radiograph, abdominal ultrasound, and pelvic MRI with no evidence of osteomyelitis. Echocardiogram showed prominent coronary arteries with lack of distal tapering. There was no evidence of coronary artery dilation or aneurysm. She had qualitatively normal biventricular function and no pericardial effusion.

After admission, the patient continued to have fevers of up to 103.6°F for a total of 14 days. She had an intermittent morbilliform rash on her face and torso occurring with fever episodes. Due to high suspicion for atypical Kawasaki disease, she was treated with intravenous immunoglobulin (IVIg) for 2 doses, acetaminophen, ketorolac, and aspirin, but continued to have daily fevers. At this point, she was diagnosed with SJIA.

Hyponatremia persisted, and on day 3, she demonstrated an Na level of 130 mEq/L with calculated serum osmolality of 278 mOsm/kg, urine osmolality of 603 mOsm/kg, and urine Na of 45 mEq/L, consistent with SIADH. Hyponatremia improved with fluid restriction, which is also consistent with SIADH (Fig 1). She was treated with intravenous solumedrol at a dose of 30 mg/kg for 2 days with resolution of fevers, and was then transitioned to oral prednisolone and discharged from the hospital. After 1 week on oral prednisolone, inflammatory markers and white blood cell counts increased, whereas Na levels decreased (Fig 1). Na levels were inversely correlated to CRP levels, suggesting that SIADH worsened with increasing inflammation. She was then started on tocilizumab infusions (12 mg/kg) every 2 weeks with improvement in these laboratory values. After 1 year, she remained afebrile, but continued to have an intermittent rash. She never experienced any desquamation of the skin. There were no adverse effects of tocilizumab.

FIGURE 1

The inverse relationship of the patient’s Na and CRP levels and response to fluid restriction and treatment are shown. Day 1 is the first day the patient presented to the hospital. Na levels increased with periods of fluid restriction and decreased when fluid restriction was discontinued. The patient was treated with intravenous steroids on days 8 and 9. Oral steroids were started on day 10 and tapered off after tocilizumab treatment was started on day 21. The patient continues to receive infusions of tocilizumab (12 mg/kg) every 2 weeks.

FIGURE 1

The inverse relationship of the patient’s Na and CRP levels and response to fluid restriction and treatment are shown. Day 1 is the first day the patient presented to the hospital. Na levels increased with periods of fluid restriction and decreased when fluid restriction was discontinued. The patient was treated with intravenous steroids on days 8 and 9. Oral steroids were started on day 10 and tapered off after tocilizumab treatment was started on day 21. The patient continues to receive infusions of tocilizumab (12 mg/kg) every 2 weeks.

Close modal

Abdominal ultrasound 1 month after presentation showed mild nonspecific splenomegaly. A follow-up echocardiogram 2 weeks after presentation continued to show prominence of the coronary arteries, in addition to a small circumferential pericardial effusion. An echocardiogram 1 month after presentation showed less prominence of the coronary arteries and resolution of the pericardial effusion, and 2 months after presentation, an echocardiogram showed normal coronary arteries without any prominence. Repeat echocardiograms remained normal in the year after presentation.

To our knowledge, this is the first reported case of SIADH in a patient with SJIA without macrophage activation syndrome (MAS). Our patient’s diagnosis was consistent with SJIA with her symptoms of arthralgia, daily fevers, evanescent rash, lymphadenopathy, splenomegaly, pericardial effusion, and elevated inflammatory markers.5 She also had a negative evaluation for infection, malignancy, and other rheumatic diseases, because SJIA is a clinical diagnosis of exclusion.5 Although the patient did not have overt arthritis, this is often absent at initial presentation.6 

MAS is a complication of systemic inflammatory disorders, including SJIA. It is characterized by laboratory abnormalities of elevated ferritin, in addition to 2 of the following: thrombocytopenia, elevated AST, hypertriglyceridemia, and decreased fibrinogen levels.7 Clinical characteristics of fever, hepatosplenomegaly, and hemorrhagic manifestations are common.7 Hyponatremia has been seen in patients with MAS due to SJIA, which is thought to be due to impaired proximal tubule reabsorption in 1 case and possibly related to SIADH in others.8 Our patient did have an elevated ferritin level, but did not meet criteria for MAS because she did not have thrombocytopenia, elevated AST, or hypertriglyceridemia.7 

Kawasaki disease was initially high on the differential diagnosis for this patient. She had multiple signs of incomplete Kawasaki disease including fever >5 days and 2 clinical symptoms (rash and cervical lymph node), and laboratory findings of a CRP level >3 mg/dL and an erythrocyte sedimentation rate >40 mm/hour, and 3 supplemental laboratory criteria (platelets >450 000 mm−3, white blood cell count >15 000 mm−3, and anemia for age with low hemoglobin).9 There are no specific diagnostic tests for Kawasaki disease or SJIA, and diagnosis can often be difficult because there are multiple overlapping symptoms. Coronary artery dilation is most often associated with Kawasaki disease, but has also been reported in patients with SJIA.10 Significantly elevated ferritin levels, as in our patient, have been found to be a useful marker to help distinguish SJIA from Kawasaki disease.11 Multiple patients with SJIA have been reported who were initially treated for Kawasaki disease due to the difficulty in distinguishing these diagnoses.12 Our patient was treated with IVIg for 2 doses without clinical improvement and continued to have daily fevers. In addition, she had persistence of inflammation despite treatment with multiple antiinflammatory medications. Patients with Kawasaki disease with a prolonged course who do not respond to IVIg are at significantly increased risk of developing coronary artery aneurysms.13 Our patient’s coronary artery abnormalities resolved after 2 weeks and did not evolve into aneurysms, despite her prolonged course of inflammation and lack of response to IVIg. Therefore, the overall clinical course is most suggestive of SJIA.

At presentation, our patient demonstrated hyponatremia with low serum osmolality and elevated urine osmolality, which is consistent with SIADH. Her hyponatremia improved temporarily during times of fluid restriction as expected in SIADH.1 It also improved after the initiation of steroids, but worsened again as the patient’s inflammatory markers increased even while receiving treatment with steroids. Hyponatremia did not resolve until SJIA was treated successfully with tocilizumab. Tocilizumab is an IL-6 receptor antibody that inhibits IL-6 activity and is effective in the treatment of severe SJIA.14 Overproduction of IL-6 plays a role in many inflammatory diseases, including SJIA. In 1 study, serum IL-6 levels were elevated in patients with active SJIA and correlated with the severity of joint involvement.15 

IL-6 has also been shown to stimulate the hypothalamic-pituitary-adrenal axis, including the release of antidiuretic hormone (ADH), in both humans and rats.3,16 In 1 study, 6 patients were treated with recombinant IL-6 as part of a clinical trial for cancer therapy.3 Pituitary hormone levels, including ADH, were subsequently monitored and showed that ADH levels increased after administration of IL-6, peaking at 15 minutes.3 The degree of ADH elevation correlated with the dose of IL-6 given. This was independent of the associated inflammatory cytokines IL-1β and tumor necrosis factor-α, which remained in the normal ranges after IL-6 administration.3 

In rats, injection of IL-6 in the brain in vivo induced ADH release.16 Intraperitoneal injection of lipopolysaccharide was also shown to induce ADH release in rats by stimulating an inflammatory response.16 Injection of anti–IL-6 antibodies in addition to the lipopolysaccharide injection inhibited this ADH release, showing that IL-6 may be the main inflammatory factor stimulating ADH release.16 In our patient, SIADH resolved after initiation of treatment with an IL-6 inhibitor, which also successfully treated her SJIA. The resolution of SIADH may have been due to the IL-6 inhibitor itself, or may have been secondary to the improvement of her inflammatory state.

Although IL-6 is implicated in the pathogenesis of both SJIA and SIADH, this is the first reported case of these conditions developing concurrently and both responding to treatment with an IL-6 inhibitor. It is difficult to ascertain whether SJIA was the direct cause of SIADH in this case; however, the evidence linking both diseases to IL-6 is a plausible mechanism connecting the two. Patients with SJIA should be monitored for SIADH to avoid complications of untreated hyponatremia.

     
  • ADH

    antidiuretic hormone

  •  
  • AST

    aspartate aminotransferase

  •  
  • CRP

    C-reactive protein

  •  
  • IL-6

    interleukin-6

  •  
  • IVIg

    intravenous immunoglobulin

  •  
  • MAS

    macrophage activation syndrome

  •  
  • Na

    sodium

  •  
  • SIADH

    syndrome of inappropriate secretion of antidiuretic hormone

  •  
  • SJIA

    systemic juvenile idiopathic arthritis

Dr Hodax was involved in the care and diagnosis of the patient, drafted the initial manuscript, and reviewed and revised the manuscript; Dr Bialo was involved in the care and diagnosis of the patient, conceptualized the components of the endocrine viewpoints of the discussion, and reviewed and revised the manuscript; Dr Yalcindag was involved in the care and diagnosis of the patient, conceptualized the components of the rheumatologic viewpoints of the discussion, and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.