Articular pain

Articular manifestations (AMs) are one of the most common extraglandular features in pSS, with a prevalence ranging from 15% to 90% . This large variability is certainly due to the different classification criteria used to select the patients, and to the different definitions chosen to characterise articular involvement in the different studies. As reported by Fauchais et al. , whose study enrolled a large cohort of patients, with pSS classified according to American-European criteria , and with articular involvement defined by the presence of arthralgias, and/or non-erosive synovitis affecting one or more peripheral joints, AMs as a whole and overt synovitis were present in 45% and 31% of patients, respectively.

AMs can precede the onset of pSS in 10–20% of the patients, although in most of them their appearance is simultaneous with the onset of sicca symptoms (40–50% of cases) . Hand small joints, wrists, knees and ankles are more frequently involved, with a symmetrical pattern of presentation in about one half of the cases having peripheral small joint involvement.

As shown by X-rays, arthritis observed in pSS is, in most cases, a non-erosive, non-evolving arthritis. The presence of erosions on X-rays should orient the diagnosis to a form of rheumatoid arthritis (RA) with associated secondary SS, mainly in the presence of anti-cyclic citrullinated peptide (CCP) antibodies. These antibodies have been described in 5–10% of patients classified as having pSS . This subset of patients who are anti-CCP positive should be clinically and radiologically monitored, in order to detect a possible evolution into an RA.

As AMs are part of the extraglandular manifestations of pSS, it is not surprising that articular involvement was reported to be associated with some of the other systemic features of the disease, such as renal involvement, cutaneous vasculitis and PN . Similarly, the presence of AMs is also associated with most of the serological markers that characterise patients with extraglandular manifestations, and mainly with the presence of cryoglobulins, hyper-γ-globulinaemia, rheumatoid factor (RF), and anti-Ro (SSA) and anti-La(SSB) antibodies .

The treatment of AMs in pSS has largely borrowed from the therapeutic approaches commonly used for RA and non-erosive arthritis of systemic lupus erythematosus. Low-dose steroids have been reported to be effective , as well as hydroxychloroquine (HCQ) in retrospective and open-label studies . However, opposite results have been obtained by using HCQ in prospective open trial . Methotrexate and leflunomide effectiveness in synovitis of patients with pSS have also been reported . Anti-tumour necrosis factor (TNF)α agents failed to demonstrate to be effective in pSS in double-blind controlled studies . It is worth noting, however, that these trials were not specifically designed to evaluate the effectiveness of these agents in AMs related to this disease.

Neuropathic pain

PNs are the most common neurological complication of pSS. PNs are clinically evident in 10–30% of patients , whilst systematic electrophysiological studies allowed documenting peripheral nerve conduction abnormalities in 20–50% of patients . Different types of PNs can be present in pSS, and they are associated with a variety of clinical symptoms, such as paraesthesias, sensory loss, ataxia, kinaesthetic impairment, motor deficits and autonomic system-related disturbances (see Table 1 ). Pain related to PNs has been rarely reported in association with sensory neuropathies, whereas in most cases neuropathic pain can be ascribed to the presence of small-fibre neuropathy (SFN).

SFN is defined as a structural abnormality of small fibres, characterised by the degeneration of their distal terminations. SFN involves small, narrow-diameter myelinated (Aδ) and unmyelinated (C) nerve fibres that are the neurological structures responsible for conveying cold and nociceptive input (Aδ fibres), innocuous warm and cold sensations, as well as high threshold mechanical, thermal and chemical stimuli (C fibres) .

Small fibres of the autonomic system can also be compromised in the course of SFN, thus leading to the concomitant presence of autonomic disturbances, such as postural hypotension, fixed tachycardia, nausea and vomiting .

Apart from distal paraesthesias that can be the initial complaint, pain is virtually always the dominant symptom of SFN. It is usually spontaneous, but it can also be evoked by no painful stimuli (allodynia), or perceived as high-intensity pain when a mild painful stimulation is applied (hyperalgesia). SFN-related pain can be extremely severe and disabling. It is often described as burning or pricking, and it can have an itching component. It usually begins at the feet, and it may more rarely involve the hands, progressing proximally and reaching a glove or a sock pattern of distribution .

The diagnosis of SFN is quite a complicated issue. The clinical suspicion evoked by the presence of typical symptoms cannot be unequivocally confirmed by neurological examination, as tendon reflex, and coordination and motor assessment appear to be perfectly normal, nor is there a test capable of revealing sensory, proprioceptive and vibratory abnormalities . Only slight alterations in thermal sensitivity can sometimes be found. Similarly, electromyography and nerve conduction studies are always inconclusive .

Fine sensory assessment by means of standardised quantitative sensory testing (QST) has been proposed for the diagnosis of SFN . However, several factors may affect the intra- and inter-observer reproducibility of this procedure. In addition, QST is unable to differentiate between peripheral and central sensory deficits, and it can be impaired by the examined patient being scarcely collaborative, or showing cognitive deficits .

Quantification of intradermal nerve fibre density has been proposed in the last years as the most valid and reliable procedure to diagnose an SFN . A skin punch biopsy of 3 mm in diameter, performed 10 cm proximal to the lateral malleolus, can provide enough skin tissue for this assessment. Immuno-histochemical techniques or immunofluorescence specific procedures are used to perform the morphometric small nerve fibre analysis. Intradermal nerve fibre density is defined as the number of fibres that cross the dermal–epidermal junction per millimetre of the epidermal surface. A decreased number of fibres under the fifth centile of the corresponding number observed in age- and sex-matched controls is seen as adequate evidence for the diagnosis of SNF .

SFN has been reported as an associated pathological condition in a large number of disorders such as diabetes mellitus and other metabolic diseases, hypothyroidism, human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections, inflammatory bowel disease, chronic renal disease, paraproteinemias, alcohol abuse, vitamin deficiencies, use of different chemotherapeutic agents and systemic autoimmune diseases, such as RA and systemic lupus erythematosus .

A number of studies have shown that SFN can also be present in around 40% of patients with pSS . Therefore, in the case of a patient with pSS complaining of burning or prickling pain in the distal parts of her/his legs or arms, without demonstration of any precise neurologic deficits by neurological examination and electrophysiological study, an SFN should be suspected, and a measurement of small fibre density should be performed in a skin sample taken from the appropriate area by punch biopsy.

The pathologic mechanisms underlying the development of SFN in pSS, as well as in other inflammatory and non-inflammatory conditions, have been only partially elucidated so far. An increased gene expression of some pro-inflammatory cytokines, such as interleukin (IL)6 and IL8, has been shown in skin biopsies of patients with SFN not related to pSS . Furthermore, potentially neurotoxic autoantibodies, such as antibodies directed against RNA-binding autoantigens of the so-called GW/P bodies , α-fodrin and type III muscarinic receptor , have also been reported to be associated with peripheral neurological involvement of pSS and then potentially operative even for SFN. Finally, a ‘vasa nervorum’ vasculitis has been demonstrated to be effective in multiple mononeuritis associated with skin vasculitis and cryoglobulinaemia . At present, no conclusive data exist to prove that one of these mechanisms is really effective in inducing SFN in the course of pSS.

Neuropathic pain

PNs are the most common neurological complication of pSS. PNs are clinically evident in 10–30% of patients , whilst systematic electrophysiological studies allowed documenting peripheral nerve conduction abnormalities in 20–50% of patients . Different types of PNs can be present in pSS, and they are associated with a variety of clinical symptoms, such as paraesthesias, sensory loss, ataxia, kinaesthetic impairment, motor deficits and autonomic system-related disturbances (see Table 1 ). Pain related to PNs has been rarely reported in association with sensory neuropathies, whereas in most cases neuropathic pain can be ascribed to the presence of small-fibre neuropathy (SFN).

SFN is defined as a structural abnormality of small fibres, characterised by the degeneration of their distal terminations. SFN involves small, narrow-diameter myelinated (Aδ) and unmyelinated (C) nerve fibres that are the neurological structures responsible for conveying cold and nociceptive input (Aδ fibres), innocuous warm and cold sensations, as well as high threshold mechanical, thermal and chemical stimuli (C fibres) .

Small fibres of the autonomic system can also be compromised in the course of SFN, thus leading to the concomitant presence of autonomic disturbances, such as postural hypotension, fixed tachycardia, nausea and vomiting .

Apart from distal paraesthesias that can be the initial complaint, pain is virtually always the dominant symptom of SFN. It is usually spontaneous, but it can also be evoked by no painful stimuli (allodynia), or perceived as high-intensity pain when a mild painful stimulation is applied (hyperalgesia). SFN-related pain can be extremely severe and disabling. It is often described as burning or pricking, and it can have an itching component. It usually begins at the feet, and it may more rarely involve the hands, progressing proximally and reaching a glove or a sock pattern of distribution .

The diagnosis of SFN is quite a complicated issue. The clinical suspicion evoked by the presence of typical symptoms cannot be unequivocally confirmed by neurological examination, as tendon reflex, and coordination and motor assessment appear to be perfectly normal, nor is there a test capable of revealing sensory, proprioceptive and vibratory abnormalities . Only slight alterations in thermal sensitivity can sometimes be found. Similarly, electromyography and nerve conduction studies are always inconclusive .

Fine sensory assessment by means of standardised quantitative sensory testing (QST) has been proposed for the diagnosis of SFN . However, several factors may affect the intra- and inter-observer reproducibility of this procedure. In addition, QST is unable to differentiate between peripheral and central sensory deficits, and it can be impaired by the examined patient being scarcely collaborative, or showing cognitive deficits .

Quantification of intradermal nerve fibre density has been proposed in the last years as the most valid and reliable procedure to diagnose an SFN . A skin punch biopsy of 3 mm in diameter, performed 10 cm proximal to the lateral malleolus, can provide enough skin tissue for this assessment. Immuno-histochemical techniques or immunofluorescence specific procedures are used to perform the morphometric small nerve fibre analysis. Intradermal nerve fibre density is defined as the number of fibres that cross the dermal–epidermal junction per millimetre of the epidermal surface. A decreased number of fibres under the fifth centile of the corresponding number observed in age- and sex-matched controls is seen as adequate evidence for the diagnosis of SNF .

SFN has been reported as an associated pathological condition in a large number of disorders such as diabetes mellitus and other metabolic diseases, hypothyroidism, human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections, inflammatory bowel disease, chronic renal disease, paraproteinemias, alcohol abuse, vitamin deficiencies, use of different chemotherapeutic agents and systemic autoimmune diseases, such as RA and systemic lupus erythematosus .

A number of studies have shown that SFN can also be present in around 40% of patients with pSS . Therefore, in the case of a patient with pSS complaining of burning or prickling pain in the distal parts of her/his legs or arms, without demonstration of any precise neurologic deficits by neurological examination and electrophysiological study, an SFN should be suspected, and a measurement of small fibre density should be performed in a skin sample taken from the appropriate area by punch biopsy.

The pathologic mechanisms underlying the development of SFN in pSS, as well as in other inflammatory and non-inflammatory conditions, have been only partially elucidated so far. An increased gene expression of some pro-inflammatory cytokines, such as interleukin (IL)6 and IL8, has been shown in skin biopsies of patients with SFN not related to pSS . Furthermore, potentially neurotoxic autoantibodies, such as antibodies directed against RNA-binding autoantigens of the so-called GW/P bodies , α-fodrin and type III muscarinic receptor , have also been reported to be associated with peripheral neurological involvement of pSS and then potentially operative even for SFN. Finally, a ‘vasa nervorum’ vasculitis has been demonstrated to be effective in multiple mononeuritis associated with skin vasculitis and cryoglobulinaemia . At present, no conclusive data exist to prove that one of these mechanisms is really effective in inducing SFN in the course of pSS.