Is syndrome of inappropriate antidiuretic hormone secretion an extra-articular manifestation of rheumatoid arthritis?

V. V. Kaushik and K. Binymin

Department of Rheumatology, Southport and Ormskirk Hospital NHS Trust, UK

Correspondence to: K. Binymin, Department of Rheumatology, Southport District General Hospital, Town Lane, Southport PR8 6PN, UK. E-mail: kbinymin2001{at}yahoo.co.uk

SIR, Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of fluid and electrolyte balance which results from the excessive release of antidiuretic hormone (ADH) that leads to hyponatraemia. Systemic diseases of many types and various groups of drugs have been associated with SIADH. The association of SIADH with rheumatoid arthritis (RA) is not very well established. We report a patient with recent onset RA and SIADH whose hyponatraemia improved upon control of the inflammatory arthritis.

An 84-yr-old woman with a background of osteoarthritis and ischaemic heart disease, who had been previously fit, well and independent, was admitted to the hospital with complaints of nausea, profound lethargy and tiredness. She had noticed increasing pain, stiffness and some swelling in her hands and feet in the 4 weeks prior to the admission. One day prior to coming into hospital she felt weak in her legs and had difficulty with standing and walking. She had no other significant past medical history. Her medications included isosorbide mononitrate, propranolol, diclofenac and low-dose aspirin. She was a non-smoker. Her examination at this point revealed synovitis of her metacarpophalangeal joints in a bilateral symmetrical distribution. She also had tenderness over her metatarsophalangeal joints. Full neurological assessment revealed generalized muscle weakness, grade 4/5, in the upper and lower limbs but there was no clinical evidence of a specific neuromuscular disorder. The rest of her examination was unremarkable. Her initial investigations revealed sodium (Na) 115 mmol/l, potassium (K) 3.9 mmol/l, urea 3.7 mmol/l and creatinine 68 mmol/l. Her full blood count showed haemoglobin (Hb) 11.5 g/dl, platelets 545 x 109/l and a white cell count (WCC) of 12.9 x 109/l. C-reactive protein (CRP) was 127.4 mg/dl and the erythrocyte sedimentation rate (ESR) was 75 mm/h.

She was fluid restricted to 1 l/day. Her diclofenac was discontinued. However, repeated measurement of Na continued to show low levels. Investigations looking into the possibility of SIADH revealed a low serum osmolality (248 mmol/kg), increased urine osmolality (334 mmol/kg) and sodium excretion (44 mmol/l) confirming the diagnosis of SIADH [1]. Further tests which included cortisol levels, a short synacthen test, thyroid function, blood glucose, myeloma screen, chest X-ray, echocardiogram and a computed tomography (CT) scan of her brain were all normal. Two weeks of fluid restriction produced only a modest improvement in her sodium levels bringing it up, at best, to 120 mmol/l.

The rheumatoid factor was strongly positive with a titre of 1/1024. The X-rays of her hands revealed peri-articular osteopenia. The rest of her autoantibody screen was negative. She satisfied American Rheumatism Association criteria [2] for a diagnosis of RA and inflammatory control was achieved initially with 120 mg of intramuscular methylprednisolone; she was later started on sulphasalazine EC. Further improvement of her RA was gradual over the following months and Fig. 1 compares her CRP and Na levels at various points in time.



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FIG. 1. The relationship between Na levels and CRP concentration in a patient with rheumatoid arthritis and syndrome of inappropriate antidiuretic hormone secretion.

 
It is clear from Fig. 1 that there was an inverse relationship between the levels of Na and CRP, reflecting the effect of active inflammation on Na levels. Furthermore, controlling disease activity with sulphasalazine EC as a monotherapy without any further long-term steroid supplement was effective in bringing the Na levels gradually toward normal values. There have been two case reports [3, 4] from Japan that discuss the occurrence of SIADH following infections in patients with RA. Their hyponatraemia resolved on treatment of their infective process. To our knowledge this is the first case to be reported where SIADH was associated with active RA, which improved on adequate control of inflammation. Based on this it is tempting to speculate that inflammation is probably responsible for increased ADH secretion through a common pathway, which when stimulated results in the release of CRP and ADH. The possibility of increased production of interleukin-6 (IL-6) in the inflammatory lesions leading to excessive release of ADH and CRP from the pituitary gland and the liver respectively has been postulated [5].

This letter raises the possibility that SIADH can occur with inflammatory conditions, and appropriate control of the underlying inflammation would lead to improvement in Na levels. At present, due to the paucity of similar reports, we recommend that hyponatraemia in patients with active RA be investigated in the traditional way in order to identify the more common causes associated with SIADH. However, in the absence of an obvious underlying cause for SIADH, the possible association with active inflammation should be considered. Furthermore, the lack of response of hyponatraemia to the standard treatment with fluid restriction is another clue to the presence of an on-going active process (inflammation in this case) responsible for propagating SIADH. Recognizing this clinical association may save patients with inflammatory arthritis going through an exhaustive list of investigations in an attempt to identify another cause for their SIADH.

The authors have declared no conflicts of interest.

References

  1. Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 1967;42:790–806.[ISI][Medline]
  2. Arnett FCS, Edworthy M, Bloch DA et al. The American Rheumatism Association Revised Criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;32:315–24.
  3. Ota K, Kumon Y, Hashimoto K. Unexpected impaired consciousness in RA: a rare complication of SIADH induced by increased IL-6. Clin Exp Rheumatol 2004;22:134.[ISI][Medline]
  4. Murakami T, Matoba H, Kuga Y, Ozawa S, Kubota K, Yoshida S. Hyponatremia in a patient with chronic inflammatory disease. Intern Med 1998;37:792–5.[ISI][Medline]
  5. Ohta M, Ito S. Hyponatremia and inflammation [in Japanese]. Rinsho Byori 1999;47:408–16.[Medline]
Accepted 27 August 2004